Mtorc1 modulators and uses thereof

ABSTRACT

The disclosure provides compounds and salts that show high selectivity and inhibitory activity for mTORC1 and uses thereof for the treatment of disease.

CROSS-REFERENCE

This application is a continuation of International Patent ApplicationPCT/US2021/024536 filed Mar. 26, 2021, which claims the benefit of U.S.Provisional Patent Applications Nos. 63/001,187 filed on Mar. 27, 2020;63/001,144 filed on Mar. 27, 2020; 63/001,177 filed on Mar. 27, 2020;63/019,176 filed on May 1, 2020; 63/054,763 filed on Jul. 21, 2020;63/054,762 filed on Jul. 21, 2020; and 63/054,768 filed Jul. 21, 2020;each of which is incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

The therapeutic potential of rapamycin has been established in manychronic diseases, from Alzheimer's and Parkinson's disease to diabetesand cardiovascular disease. However, the prohibitive safety profile ofrapamycin for chronic treatment has limited its use for the treatment ofvarious diseases. Rapamycin, an FDA approved compound, inhibits mTORsignaling, leading to extension of lifespan in a number of species, yetit can induce adverse effects, such as peripheral edema,hypercholesterolemia, muscosal ulcerations, abdominal pain, headache,nausea, diarrhea, pain, constipation, hypertriglyceridemia,hypertension, increased creatinine, fever, urinary tract infection,anemia, arthralgia, and thrombocytopenia. Given the complicationsassociated with rapamycin, new agents are needed.

SUMMARY OF THE INVENTION

In a first aspect, the present disclosure provides a compoundrepresented by the structure of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

-   R¹ is selected from —OH,

-   3- to 10-membered heterocycle, and C₃₋₁₀ carbocycle, wherein the 3-    to 10-membered heterocycle and C₃₋₁₀ carbocycle are each optionally    substituted with one or more substituents independently selected    from: hydroxy, halogen, —CN, —NO₂, ═O, C₁-C₆ alkyl, C₁-C₆ haloalkyl,    C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxy, 3- to 10-membered    heterocycle, and C₃₋₁₀ carbocycle, wherein the 3- to 10-membered    heterocycle and C₃₋₁₀ carbocycle are each optionally substituted    with one or more substituents independently selected from hydroxy,    halogen, —CN, —NO₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆    hydroxyalkyl, and C₁-C₆ alkoxy;-   R² is selected from hydrogen and an optionally substituted C₁-C₆    alkoxy, wherein substituents are independently selected at each    occurrence from hydroxy, halogen, —CN, —NO₂, C₁-C₆ alkoxy, 3- to    10-membered heterocycle, and C₃₋₁₀ carbocycle, wherein the 3- to    10-membered heterocycle and C₃₋₁₀ carbocycle are each optionally    substituted with one or more substituents independently selected    from hydroxy, halogen, —CN, —NO₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl,    C₁-C₆ hydroxyalkyl, and C₁-C₆ alkoxy; R³ is selected from hydrogen    and an optionally substituted C₁-C₆ alkoxy, wherein the substituents    are independently selected at each occurrence from hydroxy, halogen,    —CN, —NO₂, C₁-C₆ alkoxy, 3- to 10-membered heterocycle, and C₃₋₁₀    carbocycle, wherein the 3- to 10-membered heterocycle and C₃₋₁₀    carbocycle, are each optionally substituted with one or more    substituents independently selected from hydroxy, halogen, —CN,    —NO₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, and C₁-C₆    alkoxy; and-   R^(4′) is selected from,

-   R⁵ is selected from hydrogen, hydroxy, and an optionally substituted    C₁-C₆ alkoxy, wherein substituents are independently selected at    each occurrence from hydroxy, halogen, —CN, —NO₂, C₁-C₆ alkoxy, 3-    to 10-membered heterocycle, and C₃₋₁₀ carbocycle, wherein the 3- to    10-membered heterocycle, and C₃₋₁₀ carbocycle are each optionally    substituted with one or more substituents independently selected    from hydroxy, halogen, —CN, —NO₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl,    C₁-C₆ hydroxyalkyl, and C₁-C₆ alkoxy;-   R⁶ and R⁷ are each independently selected from hydrogen, hydroxy,    and C₁-C₆ alkoxy; or R⁶ and R⁷ come together to form

-   R²⁰ is selected from hydrogen and optionally substituted C₁-C₆    alkyl;-   R²¹ is selected from optionally substituted C₁-C₆ alkyl, optionally    substituted 3- to 10-membered heterocycle, and optionally    substituted C₃₋₁₀ carbocycle;-   R²² is selected from optionally substituted C₁-C₆ alkyl, optionally    substituted 3- to 10-membered heterocycle, and optionally    substituted C₃₋₁₀ carbocycle, and —P(═O)(R²⁴)₂;-   R²³ is selected from optionally substituted C₁-C₆ alkyl, optionally    substituted 3- to 10-membered heterocycle, and optionally    substituted C₃₋₁₀ carbocycle;-   R²⁴ is optionally substituted C₁-C₆ alkyl;-   R¹⁰⁰ is selected from:    -   hydrogen and —(CH₂—CH₂-G)_(y)-V; and    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, wherein each of which        is optionally substituted with one or more substituents        independently selected from halogen, —OR³¹, —SR³¹, —N(R³¹)₂,        —C(O)R³¹, —C(O)N(R³¹)₂, —N(R³¹)C(O)R³¹, —C(O)OR³¹, —OC(O)R³¹,        —S(O)R³¹, —S(O)₂R³¹, —P(O)(OR³¹)₂, —OP(O)(OR³¹)₂, —NO₂, —CN,        C₃₋₂₀ carbocycle and 3- to 20-membered heterocycle; and    -   C₃₋₂₀ carbocycle and 3- to 20-membered heterocycle each of which        is optionally substituted with one or more substituents        independently selected from halogen, —OR³¹, —SR³¹, —N(R³¹)₂,        —C(O)R³¹, —C(O)N(R³¹)₂, —N(R³¹)C(O)R³¹, —C(O)OR³¹, —OC(O)R³¹,        —S(O)R³¹, —S(O)₂R³¹, —P(O)(OR³¹)₂, —OP(O)(OR³¹)₂, —NO₂, ═O, ═S,        ═N(R³¹), —CN, C₁₋₆ alkyl, C₁₋₆ alkyl-R³¹, C₂₋₆ alkenyl, and C₂₋₆        alkynyl;-   R^(110′) is selected from:    -   hydrogen, —(CH₂—CH₂-G)_(y)-V, —S(O)R^(51′), —S(O)₂R^(51′),        —C(O)R^(51′), —C(O)N(R^(51′))₂, and —C(O)OR^(51′); and    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, wherein each of which        is optionally substituted with one or more substituents        independently selected from halogen, —OR³¹, —SR³¹, —N(R³¹)₂,        —C(O)R³¹, —C(O)N(R³¹)₂, —N(R³¹)C(O)R³¹, —C(O)OR³¹, —OC(O)R³¹,        —S(O)R³¹, —S(O)₂R³¹, —P(O)(OR³¹)₂, —OP(O)(OR³¹)₂, —NO₂, —CN,        C₃₋₂₀ carbocycle and 3- to 20-membered heterocycle; and    -   C₃₋₂₀ carbocycle and 3- to 20-membered heterocycle each of which        is optionally substituted with one or more substituents        independently selected from halogen, —OR³¹, —SR³¹, —N(R³¹)₂,        —C(O)R³¹, —C(O)N(R³¹)₂, —N(R³¹)C(O)R³¹, —C(O)OR³¹, —OC(O)R³¹,        —S(O)R³¹, —S(O)₂R³¹, —P(O)(OR³¹)₂, —OP(O)(OR³¹)₂, —NO₂, ═O, ═S,        ═N(R³¹), —CN, C₁₋₆ alkyl, C₁₋₆ alkyl-R³¹, C₂₋₆ alkenyl, and C₂₋₆        alkynyl; or-   R¹⁰⁰ and R^(110′) together with the nitrogen to which they are bound    form a 3-10-membered heterocycle optionally substituted with one or    more substituents independently selected from: hydroxy, halogen,    —CN, —NO₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, and    C₁-C₆ alkoxy, wherein when R¹ is hydroxy, the ring formed by R¹⁰⁰    and R¹¹⁰ is not unsubstituted morpholine, and wherein when one of R⁶    and R⁷ are selected from hydroxy and C₁-C₆ alkoxy or when R⁶ and R⁷    come together to form

-   the 3-10-membered heterocycle formed by R¹⁰⁰ and R¹¹⁰ is further    optionally substituted with one or more ═O;-   R¹²⁰ is selected from:    -   hydrogen, —(CH₂—CH₂-G)_(y)-V; and    -   C₃₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, each of which is        optionally substituted with one or more substituents        independently selected from halogen, —OR³¹, —SR³¹, —N(R³¹)₂,        —C(O)R³¹, —C(O)N(R³¹)₂, —N(R³¹)C(O)R³¹, —C(O)OR³¹, —OC(O)R³¹,        —S(O)R³¹, —S(O)₂R³¹, —P(O)(OR³¹)₂, —OP(O)(OR³¹)₂, —NO₂, —CN,        C₃₋₂₀ carbocycle, and 3- to 20-membered heterocycle;    -   C₃₋₂₀ saturated carbocycle and 3- to 20-membered heterocycle        each of which is optionally substituted with one or more        substituents independently selected from halogen, —OR³¹, —SR³¹,        —N(R³¹)₂, —C(O)R³¹, —C(O)N(R³¹)₂, —N(R³¹)C(O)R³¹, —C(O)OR³¹,        —OC(O)R³¹, —S(O)R³¹, —S(O)₂R³¹, —P(O)(OR³¹)₂, —OP(O)(OR³¹)₂,        —NO₂, ═O, ═S, ═N(R³¹), —CN, C₁₋₆ alkyl, C₁₋₆ alkyl-R³¹, C₂₋₆        alkenyl, and C₂₋₆ alkynyl; or    -   C₁₋₂ alkyl substituted with one or more substituents        independently selected from halogen, —OR³¹, —N(R³¹)₂, —C(O)R³¹,        —C(O)N(R³¹)₂, —N(R³¹)C(O)R³¹, —C(O)OR³¹, —OC(O)R³¹, —S(O)R³¹,        —S(O)₂R³¹, —P(O)(OR³¹)₂, —OP(O)(OR³¹)₂, —NO₂, —CN, C₃₋₂₀        carbocycle and 3- to 20-membered heterocycle;-   each G is independently selected from —O—, —NR³²—, —S—, or —SO₂—;-   each D is independently selected from —O—, —NR³²—, —S—, or —SO₂—;-   each y is selected from 3-20;-   each z is selected from 1-20;-   each V is selected from hydrogen and optionally substituted —C₁-C₆    alkyl;-   each T is selected from hydrogen and optionally substituted —C₁-C₆    alkyl;-   each R³¹ is independently selected from hydrogen, and C₁₋₁₀ alkyl,    C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocycle, and 3- to    10-membered heterocycle, each of which is optionally substituted    with one or more substituents independently selected from halogen,    —OH, —CN, —NO₂, —NH₂, ═O, ═S, C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl,    —O—C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocycle, and    3- to 10-membered heterocycle; and-   R³² is independently selected at each occurrence from: hydrogen; and    C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocycle, and 3-    to 10-membered heterocycle, each of which is optionally substituted    with one or more substituents independently selected from halogen,    —OH, —CN, —NO₂, —NH₂, ═O, ═S, C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl,    —O—C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocycle, and    3- to 10-membered heterocycle;-   wherein the optional substituents on R²⁰, R²¹, R²², R²³, R²⁴,    R^(51′), V, and T are independently selected at each occurrence    from:    -   halogen, —OR³⁰, —N(R³⁰)₂, —(O—CH₂—(CH₂)_(p))_(n)—W, —SR³⁰,        —C(O)R³⁰, —C(O)N(R³⁰)₂, —N(R³⁰)C(O)R³⁰, —C(O)OR³⁰, —OC(O)R³⁰,        —S(O)R³⁰, —S(O)₂R³⁰, —P(O)(OR³⁰)₂, —OP(O)(OR³⁰)₂, —NO₂, ═O, ═S,        ═N(R³⁰), and —CN;    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, each of which is        optionally substituted with one or more substituents        independently selected from halogen, —OR³⁰, —SR³⁰, —N(R³⁰)₂,        —C(O)R³⁰, —C(O)N(R³⁰)₂, —N(R³⁰)C(O)R³⁰, —C(O)OR³⁰, —OC(O)R³⁰,        —S(O)R³⁰, —S(O)₂R³⁰, —P(O)(OR³⁰)₂, —OP(O)(OR³⁰)₂, —NO₂, ═O, ═S,        ═N(R³⁰), —CN, C₃₋₁₀ carbocycle and 3- to 10-membered        heterocycle; and    -   C₃₋₁₀ carbocycle and 3- to 10-membered heterocycle each of which        is optionally substituted with one or more substituents        independently selected from halogen, —OR³⁰, —SR³⁰, —N(R³⁰)₂,        —C(O)R³⁰, —C(O)N(R³⁰)₂, —N(R³⁰)C(O)R³⁰, —C(O)OR³⁰, —OC(O)R³⁰,        —S(O)R³⁰, —S(O)₂R³⁰, —P(O)(OR³⁰)₂, —OP(O)(OR³⁰)₂, —NO₂, ═O, ═S,        ═N(R³⁰), —CN, C₁₋₆ alkyl, C₁₋₆ alkyl-R³⁰, C₂₋₆ alkenyl, and C₂₋₆        alkynyl;-   R³⁰ is independently selected at each occurrence from hydrogen;    C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocycle, and 3-    to 10-membered heterocycle, each of which is optionally substituted    with one or more substituents independently selected from halogen,    —OH, —CN, —NO₂, —NH₂, ═O, ═S, C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl,    —O—C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocycle, and    3- to 10-membered heterocycle;-   R^(51′) is independently selected at each occurrence from    substituted C₁₋₄ alkyl, optionally substituted C₃₋₈ carbocyle,    optionally substituted 3-10 membered heterocycle,    —((CH₂)_(q)—CH₂-D)_(z)-T and optionally substituted C₅₋₃₀ alkyl;-   q is selected from 1 to 6;-   each p is selected from 1 or 2;-   each n is selected from 3-7; and-   each W is selected from hydrogen, —OH, —C₁-C₄ alkyl and —O(C₁-C₄    alkyl).

In certain embodiments, the disclosure provides a method of treatingdisease comprising chronically administering a compound or salt ofFormula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), to a subjectin need thereof.

In certain embodiments, the disclosure provides a method of treatingdisease, wherein the disease is selected from a chronic disease. Thechronic disease may be selected from a disease wherein mTORC1 ishyperactivated. The chronic disease may be selected from a diseasewherein the the chronic disease would benefit from mTORC1 inhibition. Incertain embodiments, the chronic disease may be selected fromneurodegenerative disease, a neurocutaneous disease, aneurodevelopmental disorder, mTORopathies, tauopathies, cognitivedisorders, epilepsies, autism spectrum disorders, autoimmune diseases,metabolic diseases, cancer, diseases of impaired autophagy, infectiousdiseases, cardiovascular diseases, muscular atrophy, inflammatorydiseases, kidney diseases, pulmonary diseases, eye disorders or diseasesof aging that result in hyperactivation of mTORC1 including reducedimmune activity in the elderly. The chronic disease may be anmTORopathy, e.g., Tuberous Sclerosis.

In certain embodiments, the disclosure provides a method of treating adisease, wherein the compound may be a compound or salt of Formula (I),(IA), (IB), (IC), (ID), (IE), (IF), or (IG).

In a second aspect, the present disclosure provides a compoundrepresented by the structure of Formula (X):

-   -   or a pharmaceutically acceptable salt thereof, wherein:

-   L is selected from optionally substituted C₁₋₈ alkylene;

-   R¹ is a carboxylic acid or a carboxylic acid isostere;

-   R² is selected from hydrogen and an optionally substituted C₁-C₆    alkoxy group, wherein substituents are independently selected at    each occurrence from hydroxy, halogen, —CN, —NO₂, C₁-C₆ alkoxy, 3-    to 10-membered heterocycle, and C₃₋₁₀ carbocycle, wherein the 3- to    10-membered heterocycle and C₃₋₁₀ carbocycle are each optionally    substituted with one or more substituents independently selected    from hydroxy, halogen, —CN, —NO₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl,    C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, and C₁-C₆ alkoxy C₁-C₆ alkyl;

-   R³ is selected from hydrogen and an optionally substituted C₁-C₆    alkoxy group, wherein the substituents are independently selected at    each occurrence from hydroxy, halogen, —CN, —NO₂, C₁-C₆ alkoxy    group, 3- to 10-membered heterocycle, and C₃₋₁₀ carbocycle, wherein    the 3- to 10-membered heterocycle and C₃₋₁₀ carbocycle, are each    optionally substituted with one or more substituents independently    selected from hydroxy, halogen, —CN, —NO₂, C₁-C₆ alkyl, C₁-C₆    haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, and C₁-C₆ alkoxy C₁-C₆    alkyl; and

-   R⁴ is selected from

-   and optionally substituted 3- to 10-membered heterocycle, and when L    is optionally substituted C₃₋₈ alkylene R⁴ is further selected from    methoxy; and when -L-R¹ is ethyl acetate, tert-butyl acetate, benzyl    acetate, or methyl 2-phenylacetate, R⁴ is not methoxy;    -   wherein the optionally substituted heterocycle of R⁴ may be        substituted with one or more substituents selected from:        hydroxy, halogen, —CN, —NO₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl, ═O,        C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, and C₁-C₆ alkoxy C₁-C₆ alkyl;    -   z is 0, 1, 2, 3, 4 or 5;-   R⁵ is selected from hydrogen, hydroxy, and an optionally substituted    C₁-C₆ alkoxy group, wherein substituents are independently selected    at each occurrence from hydroxy, halogen, —CN, —NO₂, C₁-C₆ alkoxy    group, 3- to 10-membered heterocycle, and C₃₋₁₀ carbocycle, wherein    the 3- to 10-membered heterocycle, and C₃₋₁₀ carbocycle are each    optionally substituted with one or more substituents independently    selected from hydroxy, halogen, —CN, —NO₂, C₁-C₆ alkyl, C₁-C₆    haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, and C₁-C₆ alkoxy C₁-C₆    alkyl;-   R⁶ and R⁷ are each independently selected from hydrogen, hydroxy,    and C₁-C₆ alkoxy; or R⁶ and R⁷ come together to form

-   R²⁵ is independently selected at each occurrence from hydrogen,    optionally substituted C₁-C₆ alkyl, -D-(CH₂—CH₂-G)_(y)-V, optionally    substituted C₃₋₂₀ carbocycle, and optionally substituted 3- to    20-membered heterocycle;    -   wherein when R²⁵ is optionally substituted C₁-C₆ alkyl, the        substituents on C₁-C₆ alkyl are independently selected at each        occurrence from halogen, —OH, —CN, —NO₂, —NH₂, ═O, ═S,        —C(O)N(R³¹)₂, —OC(O)N(R³¹)₂, —C(O)OR³¹, —P(O)(R³¹)₂, —C₁₋₁₀        haloalkyl, —O—C₁₋₁₀ alkyl, —O—C₁₋₁₀ alkyl-CN, —O—C₁₋₁₀        alkyl-C(O)OR³¹, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₂₀ carbocycle,        and 3- to 20-membered heterocycle;    -   wherein when R²⁵ is optionally substituted C₃₋₂₀ carbocycle or        optionally substituted 3- to 20-membered heterocycle, the        substituents on C₃₋₂₀ carbocycle and 3- to 20-membered        heterocycle are independently selected at each occurrence from        halogen, —OR³¹, —SR³¹, —N(R³¹)₂, —C(O)R³¹, —C(O)N(R³¹)₂,        —N(R³¹)C(O)R³¹, —C(O)OR³¹, —OC(O)R³¹, —S(O)R³¹, —S(O)₂R³¹,        —P(O)(OR³¹)₂, —OP(O)(OR³¹)₂, —NO₂, ═O, ═S, ═N(R³¹), —CN, C₁₋₆        alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;    -   wherein D is selected from a bond or —O—;    -   each G is independently selected from —O—, —NR³²—, —S—, or        —SO₂—;    -   each y is selected from 1-20;    -   each V is selected from hydrogen and optionally substituted        —C₁-C₆ alkyl;-   R³⁰ is independently selected at each occurrence from hydrogen;    C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocycle, and 3-    to 10-membered heterocycle, each of which is optionally substituted    with one or more substituents independently selected from halogen,    —OH, —OSi(C₁-C₆alkyl)₃, —CN, —NO₂, —NH₂, ═O, ═S, C₁₋₁₀ alkyl, —C₁₋₁₀    haloalkyl, —O—C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀    carbocycle, and 3- to 10-membered heterocycle;-   R′ and R″ are independently selected at each occurrence from    hydrogen, halogen, —OR³¹, and C₁₋₈ alkyl optionally substituted with    one or more substituents independently selected from halogen and    —OR³¹; and-   R³¹ is independently selected at each occurrence from hydrogen; and    C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₂ carbocycle, and 3-    to 12-membered heterocycle, each of which is optionally substituted    with one or more substituents independently selected from halogen,    —OH, —OSi(C₁-C₆ alkyl)₃, —CN, —NO₂, —NH₂, ═O, ═S, C₁₋₁₀ alkyl,    —C₁₋₁₀ haloalkyl, —O—C₁₋₁₀ alkyl, —O—C₁₋₁₀ alkyl-OH, C₂₋₁₀ alkenyl,    C₂₋₁₀ alkynyl, C₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle.-   R³² is independently selected at each occurrence from: hydrogen; and    C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocycle, and 3-    to 10-membered heterocycle, each of which is optionally substituted    with one or more substituents independently selected from halogen,    —OH, —CN, —NO₂, —NH₂, ═O, ═S, C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl,    —O—C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocycle, and    3- to 10-membered heterocycle; and-   wherein the substituents on V and L are independently selected at    each occurrence from:    -   halogen, —OR³⁰, —N(R³⁰)₂, —SR³⁰, —C(O)R³⁰, —C(O)N(R³⁰)₂,        —N(R³⁰)C(O)R³⁰, —C(O)OR³⁰, —OC(O)R³⁰, —S(O)R³⁰, —S(O)₂R³⁰,        —P(O)(OR³⁰)₂, —OP(O)(OR³⁰)₂, —NO₂, ═O, ═S, ═N(R³⁰), and —CN;    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, each of which is        optionally substituted with one or more substituents        independently selected from halogen, —OR³⁰, —SR³⁰, —N(R³⁰)₂,        —C(O)R³⁰, —C(O)N(R³⁰)₂, —N(R³⁰)C(O)R³⁰, —C(O)OR³⁰, —OC(O)R³⁰,        —S(O)R³⁰, —S(O)₂R³⁰, —P(O)(OR³⁰)₂, —OP(O)(OR³⁰)₂, —NO₂, ═O, ═S,        ═N(R³⁰), —CN, C₃₋₁₀ carbocycle and 3- to 10-membered        heterocycle; and    -   C₃₋₁₀ carbocycle and 3- to 10-membered heterocycle each of which        is optionally substituted with one or more substituents        independently selected from halogen, —OR³⁰, —SR³⁰, —N(R³⁰)₂,        —C(O)R³⁰, —C(O)N(R³⁰)₂, —N(R³⁰)C(O)R³⁰, —C(O)OR³⁰, —OC(O)R³⁰        —S(O)R³⁰, —S(O)₂R³⁰, —P(O)(OR³⁰)₂, —OP(O)(OR³⁰)₂, —NO₂, ═O, ═S,        ═N(R³⁰), —CN, C₁₋₆ alkyl, C₁₋₆ alkyl-R³⁰, C₂₋₆ alkenyl, and C₂₋₆        alkynyl;

In certain embodiments, the disclosure provides a method of treatingdisease comprising administering, e.g., chronically administering, acompound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or(XG), to a subject in need thereof.

In certain embodiments, the disclosure provides a method of treatingdisease, wherein the disease is selected from a chronic disease. Thechronic disease may be selected from a disease wherein mTORC1 ishyperactivated. The chronic disease may be selected from a diseasewherein the the chronic disease would benefit from mTORC1 inhibition. Incertain embodiments, the chronic disease may be selected fromneurodegenerative disease, a neurocutaneous disease, aneurodevelopmental disorder, mTORopathies, tauopathies, cognitivedisorders, epilepsies, autism spectrum disorders, autoimmune diseases,metabolic diseases, cancer, diseases of impaired autophagy, infectiousdiseases, cardiovascular diseases, muscular atrophy, inflammatorydiseases, kidney diseases, pulmonary diseases, eye disorders or diseasesof aging that result in hyperactivation of mTORC1 including reducedimmune activity in the elderly. The chronic disease may be anmTORopathy, e.g., Tuberous Sclerosis.

In certain embodiments, the disclosure provides a method of treating adisease, wherein the compound may be a compound or salt of Formula (X),(XA), (XB), (XC), (XD), (XE), (XF), or (XG).

In a third aspect, the present disclosure provides a compoundrepresented by the structure of Formula L:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   R¹ is selected from

-   -   3- to 10-membered heterocycle, and C₃₋₁₀ carbocycle, wherein the        3- to 10-membered heterocycle and C₃₋₁₀ carbocycle are each        optionally substituted with one or more substituents        independently selected from R³³;    -   R² is selected from hydrogen and an optionally substituted C₁-C₆        alkoxy group, wherein substituents are independently selected at        each occurrence from hydroxy, halogen, —CN, —NO₂, C₁-C₆ alkoxy,        3- to 10-membered heterocycle, and C₃₋₁₀ carbocycle, wherein the        3- to 10-membered heterocycle and C₃₋₁₀ carbocycle are each        optionally substituted with one or more substituents        independently selected from hydroxy, halogen, —CN, —NO₂, C₁-C₆        alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, and        C₁-C₆ alkoxy C₁-C₆ alkyl;    -   R³ is selected from hydrogen and an optionally substituted C₁-C₆        alkoxy group, wherein the substituents are independently        selected at each occurrence from hydroxy, halogen, —CN, —NO₂,        C₁-C₆ alkoxy group, 3- to 10-membered heterocycle, and C₃₋₁₀        carbocycle, wherein the 3- to 10-membered heterocycle and C₃₋₁₀        carbocycle, are each optionally substituted with one or more        substituents independently selected from hydroxy, halogen, —CN,        —NO₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆        alkoxy, and C₁-C₆ alkoxy C₁-C₆ alkyl; and    -   R⁴ is

-   -   R⁵ is selected from hydrogen, hydroxy, and an optionally        substituted C₁-C₆ alkoxy group, wherein substituents are        independently selected at each occurrence from hydroxy, halogen,        —CN, —NO₂, C₁-C₆ alkoxy group, 3- to 10-membered heterocycle,        and C₃₋₁₀ carbocycle, wherein the 3- to 10-membered heterocycle,        and C₃₋₁₀ carbocycle are each optionally substituted with one or        more substituents independently selected from hydroxy, halogen,        —CN, —NO₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl,        C₁-C₆ alkoxy, and C₁-C₆ alkoxy C₁-C₆ alkyl;    -   R⁶ and R⁷ are each independently selected from hydrogen,        hydroxy, and C₁₋₆ alkoxy; or    -   R⁶ and R⁷ come together to form

-   -   R²⁰ is selected from hydrogen and optionally substituted C₁-C₆        alkyl;    -   R²¹ is selected from optionally substituted C₁-C₆ alkyl, and        optionally substituted 3 to 7-membered heterocycle;    -   R²² is selected from hydrogen, optionally substituted C₁-C₆        alkyl, —Si(R²⁴)₃, and —P(═O)(R²⁴)₂;    -   R²³ is selected from optionally substituted C₁-C₆ alkyl and        optionally substituted 3 to 7-membered heterocycle;

-   R²⁴ is optionally substituted C₁-C₆ alkyl;    -   wherein the substituents on R²⁰, R²¹, R²², R²³, and R²⁴, are        independently selected at each occurrence from:        -   halogen, —OR³⁰, —N(R³⁰)₂, —(O—CH₂—(CH₂)_(p))_(n)—W, —SR³⁰,            —N(R³⁰)₂, —C(O)R³⁰, —C(O)N(R³⁰)₂, —N(R³⁰)C(O)R³⁰, —C(O)OR³⁰,            —OC(O)R³⁰, —S(O)R³⁰, —S(O)₂R³⁰, —P(O)(OR³⁰)₂, —OP(O)(OR³⁰)₂,            —NO₂, ═O, ═S, ═N(R³⁰), and —CN;        -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, each of which is            optionally substituted with one or more substituents            independently selected from halogen, —OR³⁰, —SR³⁰, —N(R³⁰)₂,            —C(O)R³⁰, —C(O)N(R³⁰)₂, —N(R³⁰)C(O)R³⁰, —C(O)OR³⁰,            —OC(O)R³⁰, —S(O)R³⁰, —S(O)₂R³⁰, —P(O)(OR³⁰)₂, —OP(O)(OR³⁰)₂,            —NO₂, ═O, ═S, ═N(R³⁰), —CN, C₃₋₁₀ carbocycle and 3- to            10-membered heterocycle; and        -   C₃₋₁₀ carbocycle and 3- to 10-membered heterocycle each of            which is optionally substituted with one or more            substituents independently selected from halogen, —OR³⁰,            —SR³⁰, —N(R³⁰)₂, —C(O)R³⁰, —C(O)N(R³⁰)₂, —N(R³⁰)C(O)R³⁰,            —C(O)OR³⁰, —OC(O)R³⁰, —S(O)R³⁰, —S(O)₂R³⁰, —P(O)(OR³⁰)₂,            —OP(O)(OR³⁰)₂, —NO₂, ═O, ═S, ═N(R³⁰), —CN, C₁₋₆ alkyl, C₁₋₆            alkyl-R³⁰, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;    -   each p is selected from 1 or 2;    -   each n is selected from 3 to 7;    -   each W is selected from hydrogen, —OH, —C₁-C₄ alkyl, and        —O(C₁-C₄ alkyl);    -   R³⁰ is independently selected at each occurrence from:        -   hydrogen; and    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₂ carbocycle, and        3- to 12-membered heterocycle, each of which is optionally        substituted with one or more substituents independently selected        from halogen, —OH, —OSi(C₁-C₆ alkyl)₃, —CN, —NO₂, —NH₂, ═O, ═S,        C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl, —O—C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl,        C₂₋₁₀ alkynyl, C₃₋₁₂ carbocycle, 3- to 12-membered heterocycle,        and haloalkyl;    -   z is selected from 0-2;    -   R′ and R″ are independently selected from hydrogen, halogen,        —OR³¹, and C₁₋₃ alkyl optionally substituted with one or more        substituents independently selected from halogen and —OR³¹;    -   Ring A is selected from an optionally substituted C₃-C₅        carbocycle and optionally substituted 3- to 5-membered        heterocycle, wherein substituents on Ring A are independently        selected at each occurrence from:        -   halogen, —OR³¹, —SR³¹, —N(R³¹)₂, —C(O)R³¹, —C(O)N(R³¹)₂,            N(R³¹)C(O)R³¹, —C(O)OR³¹, —OC(O)R³¹, —S(O)R³¹, —S(O)₂R³¹,            —P(O)(OR³¹)₂, —OP(O)(OR³¹)₂, —NO₂, ═O, ═S, ═N(R³¹), and —CN;        -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, each of which is            optionally substituted with one or more substituents            independently selected from halogen, —OR³¹, —SR³¹, —N(R³¹)₂,            —C(O)R³¹, —C(O)N(R³¹)₂, —N(R³¹)C(O)R³¹, —C(O)OR³¹,            —OC(O)R³¹, —S(O)R³¹, —S(O)₂R³¹, —P(O)(OR³¹)₂, —OP(O)(OR³¹)₂,            —NO₂, ═O, ═S, ═N(R³¹), —CN, C₃₋₁₀ carbocycle and 3- to            10-membered heterocycle; and        -   C₃₋₁₀ carbocycle and 3- to 10-membered heterocycle each of            which is optionally substituted with one or more            substituents independently selected from halogen, —OR³¹,            —SR³¹, —N(R³¹)₂, —C(O)R³¹, —C(O)N(R³¹)₂, —N(R³¹)C(O)R³¹,            —C(O)OR³¹, —OC(O)R³¹, —S(O)R³¹, —S(O)₂R³¹, —P(O)(OR³¹)₂,            —OP(O)(OR³¹)₂, —NO₂, ═O, ═S, ═N(R³¹), —CN, C₁₋₆ alkyl, C₂₋₆            alkenyl, C₂₋₆ alkynyl;        -   R³¹ is independently selected at each occurrence from            hydrogen; and C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl,            C₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle, each of            which is optionally substituted with one or more            substituents independently selected from halogen, —OH, —CN,            —NO₂, —NH₂, ═O, ═S, C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl, —O—C₁₋₁₀            alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₂ carbocycle, and            3- to 12-membered heterocycle; and

-   R³³ is independently selected at each occurrence from hydroxy,    halogen, —CN, —NO₂, ═O, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆    hydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl, 3- to    10-membered heterocycle, and C₃₋₁₀ carbocycle, wherein the 3- to    10-membered heterocycle and C₃₋₁₀ carbocycle are each optionally    substituted with one or more substituents independently selected    from hydroxy, halogen, —CN, —NO₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl,    C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, and C₁-C₆ alkoxy C₁-C₆ alkyl.

In certain embodiments, the disclosure provides a method of treatingdisease comprising chronically administering a compound or salt ofFormula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG) to a subject inneed thereof.

In certain embodiments, the disclosure provides a method of treatingdisease, wherein the disease is selected from a chronic disease. Thechronic disease may be selected from a disease wherein mTORC1 ishyperactivated. The chronic disease may be selected from a diseasewherein the the chronic disease would benefit from mTORC1 inhibition. Incertain embodiments, the chronic disease may be selected fromneurodegenerative disease, a neurocutaneous disease, aneurodevelopmental disorder, mTORopathies, tauopathies, cognitivedisorders, epilepsies, autism spectrum disorders, autoimmune diseases,metabolic diseases, cancer, diseases of impaired autophagy, infectiousdiseases, cardiovascular diseases, muscular atrophy, inflammatorydiseases, kidney diseases, pulmonary diseases,eye disorders or diseasesof aging that result in hyperactivation of mTORC1 including reducedimmune activity in the elderly. The chronic disease may be anmTORopathy, e.g., Tuberous Sclerosis.

In certain embodiments, the disclosure provides a method of treating adisease, wherein the compound may be a compound or salt of Formula (L),(LA), (LB), (LC), (LD), (LE), (LF), or (LG).

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.To the extent publications and patents or patent applicationsincorporated by reference contradict the disclosure contained in thespecification, the specification is intended to supersede and/or takeprecedence over any such contradictory material.

DETAILED DESCRIPTION OF THE INVENTION

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. It should be understoodthat various alternatives to the embodiments of the invention describedherein may be employed in practicing the invention. It is intended thatthe following claims define the scope of the invention and that methodsand structures within the scope of these claims and their equivalents becovered thereby.

Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of skill in theart to which this invention belongs. All patents and publicationsreferred to herein are incorporated by reference.

As used in the specification and claims, the singular form “a”, “an” and“the” includes plural references unless the context clearly dictatesotherwise.

The term “C_(x-y)” when used in conjunction with a chemical moiety, suchas alkyl, alkenyl, or alkynyl is meant to include groups that containfrom x to y carbons in the chain. For example, the term “C₁₋₆alkyl”refers to saturated hydrocarbon groups, including straight-chain alkyland branched-chain alkyl groups that contain from 1 to 6 carbons. Theterm —C_(x-y)alkylene- refers to a substituted or unsubstituted alkylenechain with from x to y carbons in the alkylene chain. For example—C₁₋₆alkylene- may be selected from methylene, ethylene, propylene,butylene, pentylene, and hexylene, any one of which is optionallysubstituted.

The terms “C_(x-y)alkenyl” and “C_(x-y)alkynyl” refer to unsaturatedaliphatic groups analogous in length and possible substitution to thealkyls described above, but that contain at least one double or triplebond, respectively. The term —C_(x-y)alkenylene- refers to a substitutedor unsubstituted alkenylene chain with from x to y carbons in thealkenylene chain. For example, —C₂₋₆alkenylene- may be selected fromethenylene, propenylene, butenylene, pentenylene, and hexenylene, anyone of which is optionally substituted. An alkenylene chain may have onedouble bond or more than one double bond in the alkenylene chain. Theterm —C_(x-y)alkynylene- refers to a substituted or unsubstitutedalkynylene chain with from x to y carbons in the alkynylene chain. Forexample, —C₂₋₆alkynylene- may be selected from ethynylene, propynylene,butynylene, pentynylene, and hexynylene, any one of which is optionallysubstituted. An alkynylene chain may have one triple bond or more thanone triple bond in the alkynylene chain.

“Alkylene” refers to a straight divalent hydrocarbon chain linking therest of the molecule to a radical group, consisting solely of carbon andhydrogen, containing no unsaturation, and preferably having from one totwelve carbon atoms, for example, methylene, ethylene, propylene,butylene, and the like. The alkylene chain is attached to the rest ofthe molecule through a single bond and to the radical group through asingle bond. The points of attachment of the alkylene chain to the restof the molecule and to the radical group are through the terminalcarbons respectively. An alkylene chain may be optionally substituted byone or more substituents such as those substituents described herein.

“Alkenylene” refers to a straight divalent hydrocarbon chain linking therest of the molecule to a radical group, consisting solely of carbon andhydrogen, containing at least one carbon-carbon double bond, andpreferably having from two to twelve carbon atoms. The alkenylene chainis attached to the rest of the molecule through a single bond and to theradical group through a single bond. The points of attachment of thealkenylene chain to the rest of the molecule and to the radical groupare through the terminal carbons respectively. An alkenylene chain maybe optionally substituted by one or more substituents such as thosesubstituents described herein.

“Alkynylene” refers to a straight divalent hydrocarbon chain linking therest of the molecule to a radical group, consisting solely of carbon andhydrogen, containing at least one carbon-carbon triple bond, andpreferably having from two to twelve carbon atoms. The alkynylene chainis attached to the rest of the molecule through a single bond and to theradical group through a single bond. The points of attachment of thealkynylene chain to the rest of the molecule and to the radical groupare through the terminal carbons respectively. An alkynylene chain maybe optionally substituted by one or more substituents such as thosesubstituents described herein.

The term “carbocycle” as used herein refers to a saturated, unsaturatedor aromatic ring in which each atom of the ring is carbon. Carbocyclemay include 3- to 10-membered monocyclic rings, 6- to 12-memberedbicyclic rings, and 6- to 12-membered bridged rings. Each ring of abicyclic carbocycle may be selected from saturated, unsaturated, andaromatic rings. In some embodiments, the carbocycle is an aryl. In someembodiments, the carbocycle is a cycloalkyl. In some embodiments, thecarbocycle is a cycloalkenyl. In an exemplary embodiment, an aromaticring, e.g., phenyl, may be fused to a saturated or unsaturated ring,e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination ofsaturated, unsaturated and aromatic bicyclic rings, as valence permits,are included in the definition of carbocyclic. Exemplary carbocyclesinclude cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl,indanyl, and naphthyl. Bicyclic carbocycles may be fused, bridged orspiro-ring systems. A carbocycle may be optionally substituted by one ormore substituents such as those substituents described herein. The term“heterocycle” as used herein refers to a saturated, unsaturated oraromatic ring comprising one or more heteroatoms. Exemplary heteroatomsinclude N, O, Si, P, B, and S atoms. Heterocycles include 3- to10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6-to 12-membered bridged rings. Each ring of a bicyclic heterocycle may beselected from saturated, unsaturated, and aromatic rings. Theheterocycle may be attached to the rest of the molecule through any atomof the heterocycle, valence permitting, such as a carbon or nitrogenatom of the heterocycle. In some embodiments, the heterocycle is aheteroaryl. In some embodiments, the heterocycle is a heterocycloalkyl.In an exemplary embodiment, a heterocycle, e.g., pyridyl, may be fusedto a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, orcyclohexene. Exemplary heterocycles include pyrrolidinyl, pyrrolyl,imidazolyl, pyrazolyl, triazolyl, piperidinyl, pyridinyl, pyrimidinyl,pyridazinyl, pyrazinyl, thiophenyl, oxazolyl, thiazolyl, morpholinyl,indazolyl, indolyl, and quinolinyl. Bicyclic heterocycles may be fused,bridged or spiro-ring systems. A heterocycle may be optionallysubstituted by one or more substituents such as those substituentsdescribed herein.

The term “heteroaryl” includes aromatic single ring structures,preferably 5- to 7-membered rings, more preferably 5- to 6-memberedrings, whose ring structures include at least one heteroatom, preferablyone to four heteroatoms, more preferably one or two heteroatoms. Theterm “heteroaryl” also includes polycyclic ring systems having two ormore rings in which two or more atoms are common to two adjoining ringswherein at least one of the rings is heteroaromatic, e.g., the otherrings can be aromatic or non-aromatic carbocyclic, or heterocyclic.Heteroaryl groups include, for example, pyrrole, furan, thiophene,imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine,and pyrimidine, and the like.

The term “substituted” refers to moieties having substituents replacinga hydrogen on one or more carbons or substitutable heteroatoms, e.g., anNH or NH₂ of a compound. It will be understood that “substitution” or“substituted with” includes the implicit proviso that such substitutionis in accordance with permitted valence of the substituted atom and thesubstituent, and that the substitution results in a stable compound,i.e., a compound which does not spontaneously undergo transformationsuch as by rearrangement, cyclization, elimination, etc. In certainembodiments, substituted refers to moieties having substituentsreplacing two hydrogen atoms on the same carbon atom, such assubstituting the two hydrogen atoms on a single carbon with an oxo,imino or thioxo group. As used herein, the term “substituted” iscontemplated to include all permissible substituents of organiccompounds. In a broad aspect, the permissible substituents includeacyclic and cyclic, branched and unbranched, carbocyclic andheterocyclic, aromatic and non-aromatic substituents of organiccompounds. The permissible substituents can be one or more and the sameor different for appropriate organic compounds.

In some embodiments, substituents may include any substituents describedherein, for example: halogen, hydroxy, oxo (═O), thioxo (═S), cyano(—CN), nitro (—NO₂), imino (═N—H), oximo (═N—OH), hydrazino (═N—NH₂),—R^(b)—OR^(a), —R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a),—R^(b)—OC(O)—N(R^(a))₂, —R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a),—R^(b)—C(O)OR^(a), —R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)R^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2), and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2); and alkyl, alkenyl,alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl,and heteroarylalkyl any of which may be optionally substituted by alkyl,alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo(═O), thioxo (═S), cyano (—CN), nitro (—NO₂), imino (═N—H), oximo(═N—OH), hydrazine (═N—NH₂), —R^(b)—OR^(a), —R^(b)—OC(O)—R^(a),—R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂, —R^(b)—N(R^(a))₂,—R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a), —R^(b)—C(O)N(R^(a))₂,—R^(b)—O—R^(c)—C(O)N(R^(a))₂, —R^(b)—N(R^(a))C(O)OR^(a),—R^(b)—N(R^(a))C(O)R^(a), —R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or2), —R^(b)—S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a)(where t is 1 or 2) and —R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2);wherein each R^(a) is independently selected from hydrogen, alkyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, wherein eachR^(a), valence permitting, may be optionally substituted with alkyl,alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo(═O), thioxo (═S), cyano (—CN), nitro (—NO₂), imino (═N—H), oximo(═N—OH), hydrazine (═N—NH₂), —R^(b)—OR^(a), —R^(b)—OC(O)—R^(a),—R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂, —R^(b)—N(R^(a))₂,—R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a), —R^(b)—C(O)N(R^(a))₂,—R^(b)—O—R^(c)—C(O)N(R^(a))₂, —R^(b)—N(R^(a))C(O)OR^(a),—R^(b)—N(R^(a))C(O)R^(a), —R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or2), —R^(b)—S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a)(where t is 1 or 2) and —R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2);and wherein each R^(b) is independently selected from a direct bond or astraight or branched alkylene, alkenylene, or alkynylene chain, and eachR^(c) is a straight or branched alkylene, alkenylene or alkynylenechain. It will be understood by those skilled in the art thatsubstituents can themselves be substituted, if appropriate.

The phrases “parenteral administration” and “administered parenterally”as used herein means modes of administration other than enteral andtopical administration, usually by injection, and includes, withoutlimitation, intravenous, intramuscular, intraarterial, intrathecal,intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal,transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular,subarachnoid, intraspinal and intrasternal injection and infusion.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The phrase “pharmaceutically acceptable excipient” or “pharmaceuticallyacceptable carrier” as used herein means a pharmaceutically acceptablematerial, composition or vehicle, such as a liquid or solid filler,diluent, excipient, solvent or encapsulating material. Each carrier mustbe “acceptable” in the sense of being compatible with the otheringredients of the formulation and not injurious to the patient. Someexamples of materials which can serve as pharmaceutically acceptablecarriers include: (1) sugars, such as lactose, glucose and sucrose; (2)starches, such as corn starch and potato starch; (3) cellulose, and itsderivatives, such as sodium carboxymethyl cellulose, ethyl cellulose andcellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7)talc; (8) excipients, such as cocoa butter and suppository waxes; (9)oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil,olive oil, corn oil and soybean oil; (10) glycols, such as propyleneglycol; (11) polyols, such as glycerin, sorbitol, mannitol andpolyethylene glycol; (12) esters, such as ethyl oleate and ethyllaurate; (13) agar; (14) buffering agents, such as magnesium hydroxideand aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17)isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20)phosphate buffer solutions; and (21) other non-toxic compatiblesubstances employed in pharmaceutical formulations.

The terms “subject,” “individual,” and “patient” may be usedinterchangeably and refer to humans, the as well as non-human mammals(e.g., non-human primates, canines, equines, felines, porcines, bovines,ungulates, lagomorphs, and the like). In various embodiments, thesubject can be a human (e.g., adult male, adult female, adolescent male,adolescent female, male child, female child) under the care of aphysician or other health worker in a hospital, as an outpatient, orother clinical context. In certain embodiments, the subject may not beunder the care or prescription of a physician or other health worker.

As used herein, the phrase “a subject in need thereof” refers to asubject, as described infra, that suffers from, or is at risk for, apathology to be prophylactically or therapeutically treated with acompound or salt described herein.

The terms “administer”, “administered”, “administers” and“administering” are defined as providing a composition to a subject viaa route known in the art, including but not limited to intravenous,intraarterial, oral, parenteral, buccal, topical, transdermal, rectal,intramuscular, subcutaneous, intraosseous, transmucosal, orintraperitoneal routes of administration. In certain embodiments, oralroutes of administering a composition can be used. The terms“administer”, “administered”, “administers” and “administering” acompound should be understood to mean providing a compound of theinvention or a prodrug of a compound of the invention to the individualin need.

The term “effective amount” or “therapeutically effective amount” refersto that amount of a compound or salt described herein that is sufficientto effect the intended application including but not limited to diseasetreatment, as defined below. The therapeutically effective amount mayvary depending upon the intended application (in vitro or in vivo), orthe subject and disease condition being treated, e.g., the weight andage of the subject, the severity of the disease condition, the manner ofadministration and the like, which can readily be determined by one ofordinary skill in the art. The term can also apply to a dose that caninduce a particular response in target cells, e.g., reduction ofproliferation or down regulation of activity of a target protein. Thespecific dose can vary depending on the particular compounds chosen, thedosing regimen to be followed, whether it is administered in combinationwith other compounds, timing of administration, the tissue to which itis administered, and the physical delivery system in which it iscarried.

As used herein, “treatment” or “treating” refers to an approach forobtaining beneficial or desired results with respect to a disease,disorder, or medical condition including, but not limited to, atherapeutic benefit and/or a prophylactic benefit. In certainembodiments, treatment or treating involves administering a compound orcomposition disclosed herein to a subject. A therapeutic benefit mayinclude the eradication or amelioration of the underlying disorder beingtreated. Also, a therapeutic benefit may be achieved with theeradication or amelioration of one or more of the physiological symptomsassociated with the underlying disorder, such as observing animprovement in the subject, notwithstanding that the subject may stillbe afflicted with the underlying disorder. In certain embodiments, forprophylactic benefit, the compositions are administered to a subject atrisk of developing a particular disease, or to a subject reporting oneor more of the physiological symptoms of a disease, even though adiagnosis of this disease may not have been made. Treating can include,for example, reducing, delaying or alleviating the severity of one ormore symptoms of the disease or condition, or it can include reducingthe frequency with which symptoms of a disease, defect, disorder, oradverse condition, and the like, are experienced by a patient. Treatingcan be used herein to refer to a method that results in some level oftreatment or amelioration of the disease or condition, and cancontemplate a range of results directed to that end, including but notrestricted to prevention of the condition entirely.

In certain embodiments, the term “prevent” or “preventing” as related toa disease or disorder may refer to a compound that, in a statisticalsample, reduces the occurrence of the disorder or condition in thetreated sample relative to an untreated control sample, or delays theonset or reduces the severity of one or more symptoms of the disorder orcondition relative to the untreated control sample.

A “therapeutic effect,” as that term is used herein, encompasses atherapeutic benefit and/or a prophylactic benefit as described above. Aprophylactic effect includes delaying or eliminating the appearance of adisease or condition, delaying or eliminating the onset of symptoms of adisease or condition, slowing, halting, or reversing the progression ofa disease or condition, or any combination thereof.

The term “selective inhibition” or “selectively inhibit” as referred toa biologically active agent refers to the agent's ability topreferentially reduce the target signaling activity as compared tooff-target signaling activity, via direct or interact interaction withthe target.

Introduction

The mechanistic target of rapamycin (mTOR) signaling pathway integratesboth intracellular and extracellular signals and serves as a centralregulator of cell metabolism, growth, proliferation and survival. Inparticular, mTOR complex 1 (mTORC1) positively regulates cell growth andproliferation by promoting many anabolic processes, includingbiosynthesis of proteins, lipids and organelles, and by limitingcatabolic processes such as autophagy. Much of the knowledge aboutmTORC1 function comes from the use of the bacterial macrolide rapamycin.

Rapamycin is believed to inhibit mTORC1 directly and mTORC2 indirectlyupon chronic treatment. Recent evidence has revealed that inhibition ofmTORC1 is responsible for effects related to lifespan extension, whileinhibition of mTORC2 is uncoupled from longevity and is responsible forseveral of the adverse effects of rapamycin, such as impaired insulinsensitivity, glucose homeostasis, and lipid dysregulation.

Studies of rapamycin and related rapalogs reveal that these compoundsform binary complexes with FKB binding proteins such as FKBP12 andFKBP51. This binary complex can allosterically inhibit the functionalityof mTORC1 by binding to the FRB domain of mTOR. FKBP12 and FKBP51 directbinding assays provide a method to assess the relative binding affinityof rapalogs to the specified FKBP. While not wishing to be bound by anyparticular mechanistic theory, it may be preferred that binding of arapalog to an FKB protein, e.g., FKBP12 or FKBP51, is similar,equivalent or stronger relative to rapamycin binding to said FKBprotein.

The ternary complex formation assay provides a method to assess therelative binding affinity of the rapalog/FKB binary complex to the FRBdomain of mTOR. Different binding affinities for mTOR exhibited byrapalog/FKB complexes may result in different pharmacology and safetyprofiles relative to the known rapalogs, rapamycin and everolimus.

In certain aspects, the disclosure provides compounds and salts thereof,and methods of use for the treatment of diseases. In certainembodiments, compounds described herein are referred to as rapalogswhich refers to the shared core structure of the compounds describedherein relative to rapamycin. In certain aspects, the compoundsdescribed herein display similar direct binding properties, e.g.,similar or improved FKB binding, relative to known compounds, such asrapamycin and everolimus. In certain aspects, the compounds describedherein display altered ternary binding affinity, e.g. diminished bindingaffinity to the FRB domain of mTOR, relative to known compounds, such asrapamycin or everolimus.

In certain embodiments, compounds or salts of the disclosure areevaluated for direct binding to FKBP12 and/or FKBP51. In certainembodiments, compounds or salts of the disclosure are evaluated fortermary complex formation with MTORC1 and FKBP12. In certainembodiments, a compound or salt thereof has potent binding to FKBP12and/or FKBP51.

In certain aspects, compounds of the disclosure are grouped in CompoundGroups 1, 2, and 3. Each of these compound groups describes distinctchemical structure groupings. Any duplication of variables in one grouprelative to another group is not intended to imply interchangeabilityfor that variable with a variable of one of the other groups. Forexample, the description of R¹ in compounds of Group 1 applies only tocompounds of Group 1 and not to Group 2 or Group 3.

Compound Group 1

In a first aspect, the present disclosure provides a compoundrepresented by the structure of Formula I:

-   -   or a pharmaceutically acceptable salt thereof, wherein:

-   R¹ is selected from —OH,

-   3- to 10-membered heterocycle, and C₃₋₁₀ carbocycle, wherein the 3-    to 10-membered heterocycle and C₃₋₁₀ carbocycle are each optionally    substituted with one or more substituents independently selected    from: hydroxy, halogen, —CN, —NO₂, ═O, C₁-C₆ alkyl, C₁-C₆ haloalkyl,    C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxy, 3- to 10-membered    heterocycle, and C₃₋₁₀ carbocycle, wherein the 3- to 10-membered    heterocycle and C₃₋₁₀ carbocycle are each optionally substituted    with one or more substituents independently selected from hydroxy,    halogen, —CN, —NO₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆    hydroxyalkyl, and C₁-C₆ alkoxy;-   R² is selected from hydrogen and an optionally substituted C₁-C₆    alkoxy, wherein substituents are independently selected at each    occurrence from hydroxy, halogen, —CN, —NO₂, C₁-C₆ alkoxy, 3- to    10-membered heterocycle, and C₃₋₁₀ carbocycle, wherein the 3- to    10-membered heterocycle and C₃₋₁₀ carbocycle are each optionally    substituted with one or more substituents independently selected    from hydroxy, halogen, —CN, —NO₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl,    C₁-C₆ hydroxyalkyl, and C₁-C₆ alkoxy;-   R³ is selected from hydrogen and an optionally substituted C₁-C₆    alkoxy, wherein the substituents are independently selected at each    occurrence from hydroxy, halogen, —CN, —NO₂, C₁-C₆ alkoxy, 3- to    10-membered heterocycle, and C₃₋₁₀ carbocycle, wherein the 3- to    10-membered heterocycle and C₃₋₁₀ carbocycle, are each optionally    substituted with one or more substituents independently selected    from hydroxy, halogen, —CN, —NO₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl,    C₁-C₆ hydroxyalkyl, and C₁-C₆ alkoxy; and-   R^(4′) is selected from,

-   R⁵ is selected from hydrogen, hydroxy, and an optionally substituted    C₁-C₆ alkoxy, wherein substituents are independently selected at    each occurrence from hydroxy, halogen, —CN, —NO₂, C₁-C₆ alkoxy, 3-    to 10-membered heterocycle, and C₃₋₁₀ carbocycle, wherein the 3- to    10-membered heterocycle, and C₃₋₁₀ carbocycle are each optionally    substituted with one or more substituents independently selected    from hydroxy, halogen, —CN, —NO₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl,    C₁-C₆ hydroxyalkyl, and C₁-C₆ alkoxy;-   R⁶ and R⁷ are each independently selected from hydrogen, hydroxy,    and C₁-C₆ alkoxy; or R⁶ and R⁷ come together to form

-   R²⁰ is selected from hydrogen and optionally substituted C₁-C₆    alkyl;-   R²¹ is selected from optionally substituted C₁-C₆ alkyl, optionally    substituted 3- to 10-membered heterocycle, and optionally    substituted C₃₋₁₀ carbocycle;-   R²² is selected from optionally substituted C₁-C₆ alkyl, optionally    substituted 3- to 10-membered heterocycle, and optionally    substituted C₃₋₁₀ carbocycle, and —P(═O)(R²⁴)₂;-   R²³ is selected from optionally substituted C₁-C₆ alkyl, optionally    substituted 3- to 10-membered heterocycle, and optionally    substituted C₃₋₁₀ carbocycle;-   R²⁴ is optionally substituted C₁-C₆ alkyl;-   R¹⁰⁰ is selected from:    -   hydrogen and —(CH₂—CH₂-G)_(y)-V; and    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, wherein each of which        is optionally substituted with one or more substituents        independently selected from halogen, —OR³¹, —SR³¹, —N(R³¹)₂,        —C(O)R³¹, —C(O)N(R³¹)₂, —N(R³¹)C(O)R³¹, —C(O)OR³¹, —OC(O)R³¹,        —S(O)R³¹, —S(O)₂R³¹, —P(O)(OR³¹)₂, —OP(O)(OR³¹)₂, —NO₂, —CN,        C₃₋₂₀ carbocycle and 3- to 20-membered heterocycle; and    -   C₃₋₂₀ carbocycle and 3- to 20-membered heterocycle each of which        is optionally substituted with one or more substituents        independently selected from halogen, —OR³¹, —SR³¹, —N(R³¹)₂,        —C(O)R³¹, —C(O)N(R³¹)₂, —N(R³¹)C(O)R³¹, —C(O)OR³¹, —OC(O)R³¹,        —S(O)R³¹, —S(O)₂R³¹, —P(O)(OR³¹)₂, —OP(O)(OR³¹)₂, —NO₂, ═O, ═S,        ═N(R³¹), —CN, C₁₋₆ alkyl, C₁₋₆ alkyl-R³¹, C₂₋₆ alkenyl, and C₂₋₆        alkynyl;-   R^(110′) is selected from:    -   hydrogen, —(CH₂—CH₂-G)_(y)-V, —S(O)R^(51′), —S(O)₂R^(51′),        —C(O)R^(51′), —C(O)N(R^(51′))₂, and —C(O)OR^(51′); and    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, wherein each of which        is optionally substituted with one or more substituents        independently selected from halogen, —OR³¹, —SR³¹, —N(R³¹)₂,        —C(O)R³¹, —C(O)N(R³¹)₂, —N(R³¹)C(O)R³¹, —C(O)OR³¹, —OC(O)R³¹,        —S(O)R³¹, —S(O)₂R³¹, —P(O)(OR³¹)₂, —OP(O)(OR³¹)₂, —NO₂, —CN,        C₃₋₂₀ carbocycle and 3- to 20-membered heterocycle; and    -   C₃₋₂₀ carbocycle and 3- to 20-membered heterocycle each of which        is optionally substituted with one or more substituents        independently selected from halogen, —OR³¹, —SR³¹, —N(R³¹)₂,        —C(O)R³¹, —C(O)N(R³¹)₂, —N(R³¹)C(O)R³¹, —C(O)OR³¹, —OC(O)R³¹,        —S(O)R³¹, —S(O)₂R³¹, —P(O)(OR³¹)₂, —OP(O)(OR³¹)₂, —NO₂, ═O, ═S,        ═N(R³¹), —CN, C₁₋₆ alkyl, C₁₋₆ alkyl-R³¹, C₂₋₆ alkenyl, and C₂₋₆        alkynyl; or-   R¹⁰⁰ and R^(110′) together with the nitrogen to which they are bound    form a 3-10-membered heterocycle optionally substituted with one or    more substituents independently selected from: hydroxy, halogen,    —CN, —NO₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, and    C₁-C₆ alkoxy, wherein when R¹ is hydroxy, the ring formed by R¹⁰⁰    and R¹¹⁰ is not unsubstituted morpholine, and wherein when one of R⁶    and R⁷ are selected from hydroxy and C₁-C₆ alkoxy or when R⁶ and R⁷    come together to form

-   the 3-10-membered heterocycle formed by R¹⁰⁰ and R¹¹⁰ is further    optionally substituted with one or more ═O;-   R¹²⁰ is selected from:    -   hydrogen, —(CH₂—CH₂-G)_(y)-V; and    -   C₃₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, each of which is        optionally substituted with one or more substituents        independently selected from halogen, —OR³¹, —SR31, —N(R³¹)₂,        —C(O)R³¹, —C(O)N(R³¹)₂, —N(R³¹)C(O)R³¹, —C(O)OR³¹, —OC(O)R³¹,        —S(O)R³¹, —S(O)₂R³¹, —P(O)(OR³¹)₂, —OP(O)(OR³¹)₂, —NO₂, —CN,        C₃₋₂₀ carbocycle, and 3- to 20-membered heterocycle; and    -   C₃₋₂₀ saturated carbocycle and 3- to 20-membered heterocycle        each of which is optionally substituted with one or more        substituents independently selected from halogen, —OR³¹, —SR³¹,        —N(R³¹)₂, —C(O)R³¹, —C(O)N(R³¹)₂, —N(R³¹)C(O)R³¹, —C(O)OR³¹,        —OC(O)R³¹, —S(O)R³¹, —S(O)₂R³¹, —P(O)(OR³¹)₂, —OP(O)(OR³¹)₂,        —NO₂, ═O, ═S, ═N(R³¹), —CN, C₁₋₆ alkyl, C₁₋₆ alkyl-R³¹, C₂₋₆        alkenyl, and C₂₋₆ alkynyl; or    -   C₁₋₂ alkyl substituted with one or more substituents        independently selected from halogen, —OR³¹, —N(R³¹)₂, —C(O)R³¹,        —C(O)N(R³¹)₂, —N(R³¹)C(O)R³¹, —C(O)OR³¹, —OC(O)R³¹, —S(O)R³¹,        —S(O)₂R³¹, —P(O)(OR³¹)₂, —OP(O)(OR³¹)₂, —NO₂, —CN, C₃₋₂₀        carbocycle and 3- to 20-membered heterocycle;-   each G is independently selected from —O—, —NR³²—, —S—, or —SO₂—;-   each D is independently selected from —O—, —NR³²—, —S—, or —SO₂—;-   each y is selected from 3-20;-   each z is selected from 1-20;-   each V is selected from hydrogen and optionally substituted —C₁-C₆    alkyl;-   each T is selected from hydrogen and optionally substituted —C₁-C₆    alkyl;-   each R³¹ is independently selected from hydrogen, and C₁₋₁₀ alkyl,    C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocycle, and 3- to    10-membered heterocycle, each of which is optionally substituted    with one or more substituents independently selected from halogen,    —OH, —CN, —NO₂, —NH₂, ═O, ═S, C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl,    —O—C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocycle, and    3- to 10-membered heterocycle; and-   R³² is independently selected at each occurrence from: hydrogen; and    C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocycle, and 3-    to 10-membered heterocycle, each of which is optionally substituted    with one or more substituents independently selected from halogen,    —OH, —CN, —NO₂, —NH₂, ═O, ═S, C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl,    —O—C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocycle, and    3- to 10-membered heterocycle;-   wherein the optional substituents on R²⁰, R²¹, R²², R²³, R²⁴,    R^(51′), V, and T are independently selected at each occurrence    from:    -   halogen, —OR³⁰, —N(R³⁰)₂, —(O—CH₂—(CH₂)_(p))_(n)—W, —C(O)R³⁰,        —C(O)N(R³⁰)₂, —N(R³⁰)C(O)R³⁰, —C(O)OR³⁰, —OC(O)R³⁰, —S(O)R³⁰,        —S(O)₂R³⁰, —P(O)(OR³⁰)₂, —OP(O)(OR³⁰)₂, —NO₂, ═O, ═S, ═N(R³⁰),        and —CN;    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, each of which is        optionally substituted with one or more substituents        independently selected from halogen, —OR³⁰, —SR³⁰, —N(R³⁰)₂,        —C(O)R³⁰, —C(O)N(R³⁰)₂, —N(R³⁰)C(O)R³⁰, —C(O)OR³⁰, —OC(O)R³⁰,        —S(O)R³⁰, —S(O)₂R³⁰, —P(O)(OR³⁰)₂, —OP(O)(OR³⁰)₂, —NO₂, ═O, ═S,        ═N(R³⁰), —CN, C₃₋₁₀ carbocycle and 3- to 10-membered        heterocycle; and    -   C₃₋₁₀ carbocycle and 3- to 10-membered heterocycle each of which        is optionally substituted with one or more substituents        independently selected from halogen, —OR³⁰, —SR³⁰, —N(R³⁰)₂,        —C(O)R³⁰, —C(O)N(R³⁰)₂, —N(R³⁰)C(O)R³⁰, —C(O)OR³⁰, —OC(O)R³⁰,        —S(O)R³⁰, —S(O)₂R³⁰, —P(O)(OR³⁰)₂, —OP(O)(OR³⁰)₂, —NO₂, ═O, ═S,        ═N(R³⁰), —CN, C₁₋₆ alkyl, C₁₋₆ alkyl-R³⁰, C₂₋₆ alkenyl, and C₂₋₆        alkynyl;-   R³⁰ is independently selected at each occurrence from hydrogen;    C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocycle, and 3-    to 10-membered heterocycle, each of which is optionally substituted    with one or more substituents independently selected from halogen,    —OH, —CN, —NO₂, —NH₂, ═O, ═S, C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl,    —O—C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocycle, and    3- to 10-membered heterocycle;-   R^(51′) is independently selected at each occurrence from    substituted C₁₋₄ alkyl, optionally substituted C₃₋₈ carbocyle,    optionally substituted 3-10 membered heterocycle,    —((CH₂)_(q)—CH₂-D)_(z)-T and optionally substituted C₅₋₃₀ alkyl;-   q is selected from 1 to 6;-   each p is selected from 1 or 2;-   each n is selected from 3-7; and-   each W is selected from hydrogen, —OH, —C₁-C₄ alkyl and —O(C₁-C₄    alkyl).

In some embodiments, the compound of Formula (I) is represented byFormula (IZ):

-   -   or a pharmaceutically acceptable salt thereof, wherein:

-   R¹ is selected from —OH,

3- to 10-membered heterocycle, and C₃₋₁₀ carbocycle, wherein the 3- to10-membered heterocycle and C₃₋₁₀ carbocycle are each optionallysubstituted with one or more substituents independently selected from:hydroxy, halogen, —CN, —NO₂, ═O, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxy, 3- to 10-membered heterocycle,and C₃₋₁₀ carbocycle, wherein the 3- to 10-membered heterocycle andC₃₋₁₀ carbocycle are each optionally substituted with one or moresubstituents independently selected from hydroxy, halogen, —CN, —NO₂,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, and C₁-C₆ alkoxy;

-   R² is selected from hydrogen and an optionally substituted C₁-C₆    alkoxy, wherein substituents are independently selected at each    occurrence from hydroxy, halogen, —CN, —NO₂, C₁-C₆ alkoxy, 3- to    10-membered heterocycle, and C₃₋₁₀ carbocycle, wherein the 3- to    10-membered heterocycle and C₃₋₁₀ carbocycle are each optionally    substituted with one or more substituents independently selected    from hydroxy, halogen, —CN, —NO₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl,    C₁-C₆ hydroxyalkyl, and C₁-C₆ alkoxy;-   R³ is selected from hydrogen and an optionally substituted C₁-C₆    alkoxy, wherein the substituents are independently selected at each    occurrence from hydroxy, halogen, —CN, —NO₂, C₁-C₆ alkoxy, 3- to    10-membered heterocycle, and C₃₋₁₀ carbocycle, wherein the 3- to    10-membered heterocycle and C₃₋₁₀ carbocycle, are each optionally    substituted with one or more substituents independently selected    from hydroxy, halogen, —CN, —NO₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl,    C₁-C₆ hydroxyalkyl, and C₁-C₆ alkoxy; and-   R⁴ is selected from

-   R⁵ is selected from hydrogen, hydroxy, and an optionally substituted    C₁-C₆ alkoxy, wherein substituents are independently selected at    each occurrence from hydroxy, halogen, —CN, —NO₂, C₁-C₆ alkoxy, 3-    to 10-membered heterocycle, and C₃₋₁₀ carbocycle, wherein the 3- to    10-membered heterocycle, and C₃₋₁₀ carbocycle are each optionally    substituted with one or more substituents independently selected    from hydroxy, halogen, —CN, —NO₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl,    C₁-C₆ hydroxyalkyl, and C₁-C₆ alkoxy;-   R⁶ and R⁷ are each independently selected from hydrogen, hydroxy,    and C₁-C₆ alkoxy; or R⁶ and R⁷ come together to form

-   R²⁰ is selected from hydrogen and optionally substituted C₁-C₆    alkyl;-   R²¹ is selected from optionally substituted C₁-C₆ alkyl, optionally    substituted 3- to 10-membered heterocycle, and optionally    substituted C₃₋₁₀ carbocycle;-   R²² is selected from optionally substituted C₁-C₆ alkyl, optionally    substituted 3- to 10-membered heterocycle, and optionally    substituted C₃₋₁₀ carbocycle, and —P(═O)(R²⁴)₂;-   R²³ is selected from optionally substituted C₁-C₆ alkyl, optionally    substituted 3- to 10-membered heterocycle, and optionally    substituted C₃₋₁₀ carbocycle;-   R²⁴ is optionally substituted C₁-C₆ alkyl;-   R¹⁰⁰ is selected from:    -   hydrogen and —(CH₂—CH₂-G)_(y)-V; and    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, wherein each of which        is optionally substituted with one or more substituents        independently selected from halogen, —OR³¹, —SR³¹, —N(R³¹)₂,        —C(O)R³¹, —C(O)N(R³¹)₂, —N(R³¹)C(O)R³¹, —C(O)OR³¹, —OC(O)R³¹,        —S(O)R³¹, —S(O)₂R³¹, —P(O)(OR³¹)₂, —OP(O)(OR³¹)₂, —NO₂, —CN,        C₃₋₂₀ carbocycle and 3- to 20-membered heterocycle; and    -   C₃₋₂₀ carbocycle and 3- to 20-membered heterocycle each of which        is optionally substituted with one or more substituents        independently selected from halogen, —OR³¹, —SR³¹, —N(R³¹)₂,        —C(O)R³¹, —C(O)N(R³¹)₂, —N(R³¹)C(O)R³¹, —C(O)OR³¹, —OC(O)R³¹,        —S(O)R³¹, —S(O)₂R³¹, —P(O)(OR³¹)₂, —OP(O)(OR³¹)₂, —NO₂, ═O, ═S,        ═N(R³¹), —CN, C₁₋₆ alkyl, C₁₋₆ alkyl-R³¹, C₂₋₆ alkenyl, and C₂₋₆        alkynyl;-   R¹¹⁰ is selected from:    -   hydrogen, —(CH₂—CH₂-G)_(y)-V, —S(O)R⁵¹, —S(O)₂R⁵¹, —C(O)R⁵¹,        —C(O)N(R⁵¹)₂, and —C(O)OR⁵¹; and    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, wherein each of which        is optionally substituted with one or more substituents        independently selected from halogen, —OR³¹, —SR³¹, —N(R³¹)₂,        —C(O)R³¹, —C(O)N(R³¹)₂, —N(R³¹)C(O)R³¹, —C(O)OR³¹, —OC(O)R³¹,        —S(O)R³¹, —S(O)₂R³¹, —P(O)(OR³¹)₂, —OP(O)(OR³¹)₂, —NO₂, —CN,        C₃₋₂₀ carbocycle and 3- to 20-membered heterocycle; and    -   C₃₋₂₀ carbocycle and 3- to 20-membered heterocycle each of which        is optionally substituted with one or more substituents        independently selected from halogen, —OR³¹, —SR³¹, —N(R³¹)₂,        —C(O)R³¹, —C(O)N(R³¹)₂, —N(R³¹)C(O)R³¹, —C(O)OR³¹, —OC(O)R³¹,        —S(O)R³¹, —S(O)₂R³¹, —P(O)(OR³¹)₂, —OP(O)(OR³¹)₂, —NO₂, ═O, ═S,        ═N(R³¹), —CN, C₁₋₆ alkyl, C₁₋₆ alkyl-R³¹, C₂₋₆ alkenyl, and C₂₋₆        alkynyl; or-   R¹⁰⁰ and R¹¹⁰ together with the nitrogen to which they are bound    form a 3-10-membered heterocycle optionally substituted with one or    more substituents independently selected from: hydroxy, halogen,    —CN, —NO₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, and    C₁-C₆ alkoxy, wherein when R¹ is hydroxy, the ring formed by _(R′)°    ° _(and R)″° _(is not) unsubstituted morpholine, and wherein when    one of R⁶ and R⁷ are selected from hydroxy and C₁-C₆ alkoxy or when    R⁶ and R⁷ come together to form

-   the 3-10-membered heterocycle formed by R¹⁰⁰ and R¹¹⁰ is further    optionally substituted with one or more ═O;-   R¹²⁰ is selected from:    -   hydrogen, —(CH₂—CH₂-G)_(y)-V; and    -   C₃₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, each of which is        optionally substituted with one or more substituents        independently selected from halogen, —OR³¹, —SR³¹, —N(R³¹)₂,        —C(O)R³¹, —C(O)N(R³¹)₂, —N(R³¹)C(O)R³¹, —C(O)OR³¹, —OC(O)R³¹,        —S(O)R³¹, —S(O)₂R³¹, —P(O)(OR³¹)₂, —OP(O)(OR³¹)₂, —NO₂, —CN,        C₃₋₂₀ carbocycle, and 3- to 20-membered heterocycle; and    -   C₃₋₂₀ saturated carbocycle and 3- to 20-membered heterocycle        each of which is optionally substituted with one or more        substituents independently selected from halogen, —OR³¹, —SR³¹,        —N(R³¹)₂, —C(O)R³¹, —C(O)N(R³¹)₂, —N(R³¹)C(O)R³¹, —C(O)OR³¹,        —OC(O)R³¹, —S(O)R³¹, —S(O)₂R³¹, —P(O)(OR³¹)₂, —OP(O)(OR³¹)₂,        —NO₂, ═O, ═S, ═N(R³¹), —CN, C₁₋₆ alkyl, C₁₋₆ alkyl-R³¹, C₂₋₆        alkenyl, and C₂₋₆ alkynyl; or    -   C₁₋₂ alkyl substituted with one or more substituents        independently selected from halogen, —OR³¹, —N(R³¹)₂, —C(O)R³¹,        —C(O)N(R³¹)₂, —N(R³¹)C(O)R³¹, —C(O)OR³¹, —OC(O)R³¹, —S(O)R³¹,        —S(O)₂R³¹, —P(O)(OR³¹)₂, —OP(O)(OR³¹)₂, —NO₂, —CN, C₃₋₂₀        carbocycle and 3- to 20-membered heterocycle;-   each G is independently selected from —O—, —NR³²—, —S—, or —SO₂—;-   each D is independently selected from —O—, —NR³²—, —S—, or —SO₂—;-   each y is selected from 3-20;-   each z is selected from 1-20;-   each V is selected from hydrogen and optionally substituted —C₁-C₆    alkyl;-   each T is selected from hydrogen and optionally substituted —C₁-C₆    alkyl;-   each R³¹ is independently selected from hydrogen, and C₁₋₁₀ alkyl,    C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocycle, and 3- to    10-membered heterocycle, each of which is optionally substituted    with one or more substituents independently selected from halogen,    —OH, —CN, —NO₂, —NH₂, ═O, ═S, C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl,    —O—C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocycle, and    3- to 10-membered heterocycle; and-   R³² is independently selected at each occurrence from: hydrogen; and    C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocycle, and 3-    to 10-membered heterocycle, each of which is optionally substituted    with one or more substituents independently selected from halogen,    —OH, —CN, —NO₂, —NH₂, ═O, ═S, C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl,    —O—C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocycle, and    3- to 10-membered heterocycle;-   wherein the optional substituents on R²⁰, R²¹, R²², R²³, R²⁴, R⁵¹,    V, and T are independently selected at each occurrence from:    -   halogen, —OR³⁰, —N(R³⁰)₂, —(O—CH₂—(CH₂)_(p))_(n)—W, —SR³⁰,        —C(O)R³⁰, —C(O)N(R³⁰)₂, —N(R³⁰)C(O)R³⁰, —C(O)OR³⁰, —OC(O)R³⁰,        —S(O)R³⁰, —S(O)₂R³⁰, —P(O)(OR³⁰)₂, —OP(O)(OR³⁰)₂, —NO₂, ═O, ═S,        ═N(R³⁰), and —CN;    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, each of which is        optionally substituted with one or more substituents        independently selected from halogen, —OR³⁰, —SR³⁰, —N(R³⁰)₂,        —C(O)R³⁰, —C(O)N(R³⁰)₂, —N(R³⁰)C(O)R³⁰, —C(O)OR³⁰, —OC(O)R³⁰,        —S(O)R³⁰, —S(O)₂R³⁰, —P(O)(OR³⁰)₂, —OP(O)(OR³⁰)₂, —NO₂, ═O, ═S,        ═N(R³⁰), —CN, C₃₋₁₀ carbocycle and 3- to 10-membered        heterocycle; and    -   C₃₋₁₀ carbocycle and 3- to 10-membered heterocycle each of which        is optionally substituted with one or more substituents        independently selected from halogen, —OR³⁰, —SR³⁰, —N(R³⁰)₂,        —C(O)R³⁰, —C(O)N(R³⁰)₂, —N(R³⁰)C(O)R³⁰, —C(O)OR³⁰, —OC(O)R³⁰,        —S(O)R³⁰, —S(O)₂R³⁰, —P(O)(OR³⁰)₂, —OP(O)(OR³⁰)₂, —NO₂, ═O, ═S,        ═N(R³⁰), —CN, C₁₋₆ alkyl, C₁₋₆ alkyl-R³⁰, C₂₋₆ alkenyl, and C₂₋₆        alkynyl;-   R³⁰ is independently selected at each occurrence from hydrogen;    C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocycle, and 3-    to 10-membered heterocycle, each of which is optionally substituted    with one or more substituents independently selected from halogen,    —OH, —CN, —NO₂, —NH₂, ═O, ═S, C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl,    —O—C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocycle, and    3- to 10-membered heterocycle;-   R⁵¹ is independently selected at each occurrence from    —((CH₂)_(q)—CH₂-D)_(z)-T and optionally substituted C₅₋₃₀ alkyl;-   q is selected from 1 to 6;-   each p is selected from 1 or 2;-   each n is selected from 3-7; and-   each W is selected from hydrogen, —OH, —C₁-C₄ alkyl and —O(C₁-C₄    alkyl).

In certain embodiments, the compound of Formula (I) is represented byFormula (IA):

or a salt thereof.

In certain embodiments, the compound of Formula (I) is represented byFormula (IB):

or a salt thereof.

In certain embodiments, the compound of Formula (I) is represented byFormula (IC):

or a salt thereof.

In certain embodiments, the compound of Formula (I) is represented byFormula (ID):

or a salt thereof.

In certain embodiments, the compound of Formula (I) is represented byFormula (IE):

or a salt thereof.

In certain embodiments, the compound of Formula (I) is represented byFormula (IF):

or a salt thereof.

In certain embodiments, the compound of Formula (I) is represented byFormula (IG):

or a salt thereof.

In some embodiments, for the compound or salt of Formula (I), (IA),(IB), (IC), (ID), (IE), (IF), or (IG), R^(51′) is represented by R⁵¹.

In some embodiments, for the compound or salt of Formula (I), (IA),(IB), (IC), (ID), (IE), (IF), or (IG), R^(100′) is represented by R¹⁰⁰.

In some embodiments, for the compound or salt of Formula (I), (IA),(IB), (IC), (ID), (IE), (IF), or (IG), R^(4′) is R⁴.

In some embodiments, for the compound or salt of Formula (I), (IA),(IB), (IC), (ID), (IE), (IF), or (IG),

is represented by

In some embodiments, for the compound or salt of Formula (I), (IA),(IB), (IC), (ID), (IE), (IF), or (IG), R¹⁰⁰ and R^(110′) come togetherwith the nitrogen to which they are bound form a 3-10-memberedheteroaryl optionally substituted with one or more substituentsindependently selected from: hydroxy, halogen, —CN, —NO₂, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, and C₁-C₆ alkoxy.

In some embodiments, for the compound or salt of Formula (I), (IA),(IB), (IC), (ID), (IE), (IF), or (IG), R¹⁰⁰ and R^(110′) together withthe nitrogen to which they are bound form a 3-10-membered heterocycleoptionally substituted with one or more substituents independentlyselected from: hydroxy, halogen, —CN, —NO₂, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ hydroxyalkyl, and C₁-C₆ alkoxy, wherein when R¹ ishydroxy, the ring formed by R¹⁰⁰ and R¹¹⁰ is not unsubstitutedmorpholine.

In some embodiments, for the compound or salt of Formula (I), (IA),(IB), (IC), (ID), (IE), (IF), or (IG), R¹⁰⁰ and R^(110′) come togetherwith the nitrogen to which they are bound form a 3-5 membered saturatedheterocycle optionally substituted with one or more substituentsindependently selected from: hydroxy, halogen, —CN, —NO₂, C₁-C₆ alkyl,C₁-C₆haloalkyl, C₁-C₆ hydroxyalkyl, and C₁-C₆ alkoxy.

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), when R⁶ and R⁷ cometogether to form

and R¹ is hydroxy, R⁴ is not

and when R⁶ and R⁷ come together to form

and R¹ is

R⁴ is not

In some cases, R⁴ is not

In some cases, R⁴ is not

In some cases, R⁴ is not

In some cases, R⁴ may not be

In some embodiments, for the compound or salt of Formula (I), (IA),(IB), (IC), (ID), (IE), (IF), or (IG), R¹⁰⁰ and R^(110′) do not cometogether with the nitrogen to which they are bound to form a3-10-membered ring.

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R⁴ is

In some embodiments, R¹⁰⁰ is selected from the same moiety as R¹¹⁰, forexample, R¹⁰⁰ is ethyl and R¹¹⁰ is ethyl. In some embodiments, R¹⁰⁰ isdifferent than R¹¹⁰. In some embodiments, R¹⁰⁰ is H. In someembodiments, R¹¹⁰ is selected from: —(CH₂—CH₂-G)_(y)-V; and C₁₋₁₀ alkyloptionally substituted with one or more substituents independentlyselected from halogen, —OR³¹, —SR³¹, —N(R³¹)₂, —C(O)R³¹, —C(O)N(R³¹)₂,—N(R³¹)C(O)R³¹, —C(O)OR³¹, —OC(O)R³¹, —S(O)R³¹, —S(O)₂R³¹, —P(O)(OR³¹)₂,—OP(O)(OR³¹)₂, —NO₂, —CN, C₃₋₂₀ carbocycle and 3- to 20-memberedheterocycle.

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R⁴ is

and R¹¹⁰ is selected from —(CH₂—CH₂-G)_(y)-V. In some embodiments, y of—(CH₂—CH₂-G)_(y)-V is 1 to 1000. In some embodiments, y is 1 to 800. Insome embodiments, y is 1 to 500. In some embodiments, y is 1 to 300. Insome embodiments, y is 1 to 100. In some embodiments, y is 1 to 50. Insome embodiments, y is 1 to 25. In some embodiments, y is 3 to 1000. Insome embodiments, y is 10 to 1000. In some embodiments, y is 50 to 1000.In some embodiments, y is 100 to 1000. In some embodiments, y is 200 to1000. In some embodiments, y is 500 to 1000. In some embodiments, y of—(CH₂—CH₂-G)_(y)-V for R¹¹⁰ is 3 to 10. In some embodiments, y of—(CH₂—CH₂-G)_(y)-V for R¹¹⁰ is 5 to 10. In some embodiments, y is 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, or100.

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R⁴ is

and R¹¹⁰ is selected from —(CH₂—CH₂-G)_(y)-V, wherein G of—(CH₂—CH₂-G)_(y)-V is —O—. In some embodiments, each G of—(CH₂—CH₂-G)_(y)-V for R¹¹⁰ is —NR³²—. In some embodiments, each R³² of—NR³²— is independently selected from hydrogen; and C₁₋₁₀ alkyl, each ofwhich is optionally substituted with one or more substituentsindependently selected from halogen, —OH, C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl,and —O—C₁₋₁₀ alkyl.

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R⁴ is

and R¹¹⁰ is selected from —(CH₂—CH₂-G)_(y)-V, wherein each V of R¹¹⁰ isoptionally substituted —C₁-C₁₀ alkyl. In some embodiments, each V ofR¹¹⁰ is optionally substituted —C₁-C₆ alkyl. In some embodiments, the—C₁-C₆ alkyl on V of R¹¹⁰ is optionally substituted with one or moresubstituents independently selected from halogen, —OR³⁰, —N(R³⁰)₂,—(O—CH₂—(CH₂)_(p))_(n)—W, —SR⁺, —C(O)R³⁰, —C(O)N(R³⁰)₂, —N(R³⁰)C(O)R³⁰,—C(O)OR³⁰, —OC(O)R³⁰, —S(O)R³⁰, —S(O)₂R³⁰, —P(O)(OR³⁰)₂, —OP(O)(OR³⁰ )₂,—NO₂, ═O, ═S, ═N(R³⁰), and —CN.

In some embodiments, for the compound or salt of Formula (I), (IA),(IB), (IC), (ID), (IE), (IF), or (IG), —C₁-C₆ alkyl on V of R¹¹⁰ issubstituted with one or more substituents independently selected from—OR³⁰ and —N(R³⁰)₂. In some embodiments, the —C₁-C₆ alkyl on V of R¹¹⁰is substituted with one or more —N(R³⁰)₂. In some embodiments, the—C₁-C₆ alkyl on V of R¹¹⁰ is substituted with one or more —OR³⁰. In someembodiments, each R³⁰ is selected from hydrogen; and C₁₋₅ alkyl, C₃₋₆carbocycle, and 3- to 6-membered heterocycle, each of which isoptionally substituted with one or more substituents independentlyselected from halogen, —OH, —CN, —NO₂, —NH₂, ═O, ═S, C₁₋₁₀ alkyl, —C₁₋₁₀haloalkyl, and —O—C₁₋₁₀ alkyl.

In some embodiments, for the compound or salt of Formula (I), (IA),(IB), (IC), (ID), (IE), (IF), or (IG), R⁴ is

and R¹⁰⁰ and R¹¹⁰ of

come together with the nitrogen to which they are bound form a 3-, 4-,5-, 7-, or 8-membered heterocycle optionally substituted with one ormore substituents independently selected from: hydroxy, halogen, —CN,—NO₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, and C₁-C₆alkoxy. In some embodiments, the 3- to 8-heterocycle is unsaturated. Insome embodiments, the 3- to 8-heterocycle is saturated.

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R⁴ is

wherein R¹⁰⁰ and R¹¹⁰ together with the nitrogen to which they are boundform a 3-10-membered heterocycle optionally substituted with one or moresubstituents independently selected from: hydroxy, halogen, —CN, —NO₂,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, and C₁-C₆ alkoxy,wherein when R¹ is hydroxy, the ring formed by R¹⁰⁰ and R¹¹⁰ is notunsubstituted morpholine, and wherein when one of R⁶ and R⁷ are selectedfrom hydroxy and C₁-C₆ alkoxy or when R⁶ and R⁷ come together to form

the 3-10-membered heterocycle formed by R¹⁰⁰ and R¹¹⁰ is furtheroptionally substituted with one or more ═O.

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R⁴ is

wherein R¹⁰⁰ and R¹¹⁰ together with the nitrogen to which they are boundform a 3-10-membered heterocycle optionally substituted with one or moresubstituents independently selected from: hydroxy, halogen, —CN, —NO₂,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, and C₁-C₆ alkoxy,wherein when R¹ is hydroxy, the ring formed by R¹⁰⁰ and R¹¹⁰ issubstituted morpholine, and wherein when one of R⁶ and R⁷ are selectedfrom hydroxy and C₁-C₆ alkoxy or when R⁶ and R⁷ come together to form

the 3-10-membered heterocycle formed by R¹⁰⁰ and R¹¹⁰ is furtheroptionally substituted with one or more ═O.

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R⁴ is

wherein R¹⁰⁰ and R¹¹⁰ together with the nitrogen to which they are boundform a heterocycle. The heterocycle may be selected from a 3-10-memberedheterocycle, 3-8-membered heterocycle, 3-6-membered heterocycle,3-5-membered heterocycle, 4-10-membered heterocycle, 4-8-memberedheterocycle, 4-6-membered heterocycle, and 4-5-membered heterocycle, anyof which is optionally substituted with one or more substituentsindependently selected from: hydroxy, halogen, —CN, —NO₂, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, ═O, and C₁-C₆ alkoxy. In someembodiments, the heterocycle is optionally substituted with one or moresubstituents selected from hydroxy, halogen, —CN, —NO₂, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, and C₁-C₆ alkoxy. In someembodiments, the heterocycle is optionally substituted with one or moresubstituents selected from hydroxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆hydroxyalkyl, ═O, and C₁-C₆ alkoxy. In some embodiments, the heterocycleis unsaturated. In some embodiments, the heterocycle is saturated. Insome embodiments, the heterocycle is aromatic. In some embodiments, theheterocycle further comprises at least a second heteroatom. In someembodiments, the second heteroatom is selected from nitrogen, oxygen,and sulfur. In some embodiments, the second heteroatom is selected fromnitrogen and sulfur. In some embodiments, the second heteroatom isselected from oxygen and sulfur. In some embodiments, the secondheteroatom is selected from nitrogen and oxygen. In some embodiments,the second hetereoatom is sulfur. In some embodiments, the secondheteroatom is nitrogen. In some embodiments, the second heteroatom isoxygen.

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R⁴ is

wherein R¹⁰⁰ and R¹¹⁰ together with the nitrogen to which they are boundform a 3-10-membered heterocycle optionally substituted with one or moresubstituents independently selected from: hydroxy, halogen, —CN, —NO₂,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, and C₁-C₆ alkoxy,wherein when R¹ is hydroxy, the ring formed by R¹⁰⁰ and R¹¹⁰ is not

and wherein when one of R⁶ and R⁷ are selected from hydroxy and C₁-C₆alkoxy or when R⁶ and R⁷ come together to form

the 3-10-membered heterocycle formed by R¹⁰⁰ and R¹¹⁰ is furtheroptionally substituted with one or more ═O.

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R⁴ is

and, R¹⁰⁰ and R¹¹⁰ of

come together with the nitrogen to which they are bound form anaziridine, 2H-azirine, azetidine, 2,3-dihydroazete, 1,3-diazetidine,pyrrolidine, 2-pyrroline, 2H-pyrrole, 1H-pyrrole, pyrazolidine,imidazolidine, 2-pyrazoline, 2-imidazoline, pyrazole, imidazole,1,2,4-triazole, 1,2,3-triazole, tetrazole, oxazole, isoxazole,isothiazole, thiazole, 1,2,5-oxadiazole, 1,2,3-oxadiazole,1,3,4-thiadiazole, 1,2,5-thiadiazole, 2,4-thiazolidinedione,succinimide, oxazine, thiomorpholine, thiazine, 2-oxazolidone,hydantoin, cytosine, thymine, uracil, thiomorpholine dioxide,piperidine, pyridine, piperazine, pyridazine, pyrimidine, pyrazine,triazine, 2,3-dihydroazepine, 2,5-dihydroazepine, 4,5-dihydroazepine,azepine, 2H-azepine, 3H-azepine, 4H-azepine, 1,2-diazepine,1,3-dizepine, 1,4-diazepine, 1,4-thiazepine, azocane, and azocine, eachof which is optionally substituted with one or more substituentsindependently selected from: hydroxy, halogen, —CN, —NO₂, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, and C₁-C₆ alkoxy.

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R⁴ is

and, R¹⁰⁰ and R¹¹⁰ of

come together with the nitrogen to which they are bound to form anaziridine, 2H-azirine, azetidine, 2,3-dihydroazete, 1,3-diazetidine,pyrrolidine, 2-pyrroline, 2H-pyrrole, 1H-pyrrole, pyrazolidine,imidazolidine, 2-pyrazoline, 2-imidazoline, pyrazole, imidazole,1,2,4-triazole, 1,2,3-triazole, tetrazole, oxazole, isoxazole,isothiazole, thiazole, 1,2,5-oxadiazole, 1,2,3-oxadiazole,1,3,4-thiadiazole, 1,2,5-thiadiazole, 2,4-thiazolidinedione,succinimide, oxazine, thiomorpholine, thiazine, 2-oxazolidone,hydantoin, cytosine, thymine, uracil, thiomorpholine dioxide,piperidine, pyridine, piperazine, pyridazine, pyrimidine, pyrazine,triazine, 2,3-dihydroazepine, 2,5-dihydroazepine, 4,5-dihydroazepine,azepine, 2H-azepine, 3H-azepine, 4H-azepine, 1,2-diazepine,1,3-dizepine, 1,4-diazepine, 1,4-thiazepine, azocane, azocine,1,2-thiazetidine, isothiazolidine, and imidazolidine, each of which isoptionally substituted with one or more substituents independentlyselected from: hydroxy, halogen, —CN, —NO₂, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ hydroxyalkyl, and C₁-C₆ alkoxy.

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R⁴ is

and, R¹⁰⁰ and R¹¹⁰ of

come together with the nitrogen to which they are bound to form anaziridine, 2H-azirine, azetidine, 2,3-dihydroazete, 1,3-diazetidine,pyrrolidine, 2-pyrroline, 2H-pyrrole, 1H-pyrrole, pyrazolidine,imidazolidine, 2-pyrazoline, 2-imidazoline, pyrazole, imidazole,1,2,4-triazole, 1,2,3-triazole, tetrazole, oxazole, isoxazole,isothiazole, thiazole, 1,2,5-oxadiazole, 1,2,3-oxadiazole,1,3,4-thiadiazole, 1,2,5-thiadiazole, 2,4-thiazolidinedione,succinimide, oxazine, thiomorpholine, thiazine, 2-oxazolidone,hydantoin, cytosine, thymine, uracil, thiomorpholine dioxide,piperidine, pyridine, piperazine, pyridazine, pyrimidine, pyrazine,triazine, 2,3-dihydroazepine, 2,5-dihydroazepine, 4,5-dihydroazepine,azepine, 2H-azepine, 3H-azepine, 4H-azepine, 1,2-diazepine,1,3-dizepine, 1,4-diazepine, 1,4-thiazepine, azocane, azocine,1,2-thiazetidine, isothiazolidine, and imidazolidine, each of which isoptionally substituted with one or more substituents independentlyselected from: hydroxy, halogen, —CN, —NO₂, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ hydroxyalkyl, ═O, and C₁-C₆ alkoxy.

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R⁴ is

and, R¹⁰⁰ and R¹¹⁰ of

come together with the nitrogen to which they are bound to formazetidine, 1,2-thiazetidine, isothiazolidine, and imidazolidine, each ofwhich is optionally substituted with one or more substituentsindependently selected from: hydroxy, halogen, —CN, —NO₂, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, ═O, when one of R⁶and R⁷ are selected from hydroxy and C₁-C₆ alkoxy or when R⁶ and R⁷ cometogether to form

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R⁴ is

and, R¹⁰⁰ and R¹¹⁰ of

come together with the nitrogen to which they are bound to form

and one of R⁶ and R⁷ are selected from hydroxy and C₁-C₆ alkoxy or R⁶and R⁷ come together to form

In some embodiments. for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R⁴ is

and, R¹⁰⁰ and R¹¹⁰ of

come together with the nitrogen to which they are bound to form

when one of R⁶ and R⁷ are selected from hydroxy and C₁-C₆ alkoxy or whenR⁶ and R⁷ come together to form

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R⁴ is

and, R¹⁰⁰ and R¹¹⁰ of

come together with the nitrogen to which they are bound to form

and R¹ is not selected from

In some embodiments, for the compound or salt of Formula (I), (IA),(IB), (IC), (ID), (IE), (IF), or (IG), R⁴ is

and, R¹⁰⁰ and R¹¹⁰ of

come together with the nitrogen to which they are bound to form

when R¹ is not selected from

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R⁴ is

and, R¹⁰⁰ and R¹¹⁰ of

come together with the nitrogen to which they are bound to form

when R¹ is not selected from

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R⁴ is

and, R¹⁰⁰ and R¹¹⁰ of

come together with the nitrogen to which they are bound to form

when R¹ is not selected from

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R⁴ is

and, R¹⁰⁰ and R¹¹⁰ of

come together with the nitrogen to which they are bound form anazetidine-2-one, thizetidine 1,1-dioxide, or isothiazolidine1,1-dioxide, any of which is substituted with one or more substituentsindependently selected from: hydroxy, halogen, —CN, —NO₂, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, and C₁-C₆ alkoxy.

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R⁴ is

wherein R¹⁰⁰ is hydrogen or C₁₋₁₀ alkyl; and R¹¹⁰ is selected from—(CH₂—CH₂-G)_(y)-V, —S(O)R⁵¹, —S(O)₂R⁵¹, —C(O)R⁵¹, —C(O)N(R⁵¹)₂, and—C(O)OR⁵¹; or R¹⁰⁰ and R¹¹⁰ together with the nitrogen to which they arebound form a 3-10-membered heterocycle optionally substituted with oneor more substituents selected from: hydroxy, halogen, —CN, —NO₂, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, and C₁-C₆ alkoxy, and ═O.

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R⁴ is

wherein R¹⁰⁰ is hydrogen or C₁₋₁₀ alkyl; and R¹¹⁰ is selected from—(CH₂—CH₂-G)_(y)-V, —S(O)R⁵¹, and —S(O)₂R⁵¹; or R¹⁰⁰ and R¹¹⁰ togetherwith the nitrogen to which they are bound form a 3-10-memberedheterocycle optionally substituted with one or more substituentsselected from: hydroxy, halogen, —CN, —NO₂, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ hydroxyalkyl, and C₁-C₆ alkoxy, and ═O.

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R⁴ is

wherein R¹⁰⁰ is hydrogen or C₁₋₁₀ alkyl; and R¹¹⁰ is selected from—S(O)R⁵¹, and —S(O)₂R⁵¹; or R¹⁰⁰ and R¹¹⁰ together with the nitrogen towhich they are bound form a 3-10-membered heterocycle optionallysubstituted with one or more substituents selected from: hydroxy,halogen, —CN, —NO₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl,and C₁-C₆ alkoxy, and ═O.

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R⁴ is

wherein R¹⁰⁰ is hydrogen or C₁₋₁₀ alkyl; and R¹¹⁰ is selected from—S(O)R⁵¹, and —S(O)₂R⁵¹; or R¹⁰⁰ and R¹¹⁰ together with the nitrogen towhich they are bound form a 3-10-membered heterocycle optionallysubstituted with one or more substituents selected from: hydroxy,halogen, —CN, —NO₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl,and C₁-C₆ alkoxy, and ═O.

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R⁵¹ is independentlyselected at each occurrence from —((CH₂)_(q)—CH₂-D)_(z)-T and optionallysubstituted C₅₋₃₀ alkyl; wherein q is independently selected at at eachoccurrence from 1 to 6, each D is independently selected from —O—,—NR³²—, —S—, or —SO₂—; each z is selected from 1-20; and each T isselected from hydrogen and optionally substituted —C₁-C₆ alkyl. In someembodiments, R⁵¹, is independently selected at each occurrence from—((CH₂)_(q)—CH₂-D)_(z)-T. In some embodiments, R⁵¹, is optionallysubstituted C₅₋₃₀ alkyl. In some embodiments, q is independentlyselected at at each occurrence from 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1to 2. In some embodiments, q is 1 to 5. In some embodiments, q is 1 to4. In some embodiments, q is 1 to 3. In some embodiments, q is 1 to 2.In some embodiments, q is 6. In some embodiments, q is 5. In someembodiments, q is 4. In some embodiments, q is 3. In some embodiments, qis 2. In some embodiments, q is 1. In some embodiments, D isindependently selected at each occurrence from —O—, —NR³²—, or —SO₂—. Insome embodiments, D is independently selected at each occurrence from—O—, —NR³²—, or —SO₂—. In some embodiments, D is independently selectedat each occurrence from —O— or —NR³². In some embodiments, D isindependently selected at each occurrence from —O—. In some embodiments,z is selected from 1 to 500. In some embodiments, z is selected from 1to 50. In some embodiments, z is selected from 1 to 300. In someembodiments, z is selected from 3 to 500. In some embodiments, z isselected from 3 to 250. In some embodiments, z is selected from 3 to 50.In some embodiments, z is selected from 3 to 25. In some embodiments, zis selected from 3 to 20. In some embodiments, z is selected from 3 to10. In some embodiments, z is selected from 3. In some embodiments, z isselected from 20. In some embodiments, T is is selected from hydrogenand optionally substituted —C₁-C₆ alkyl. In some embodiments, T ishydrogen. In some embodiments, T is selected from optionally substituted—C₁-C₆ alkyl. In some embodiments, T is selected from unsubstituted—C₁-C₆ alkyl. In some embodiments, R³² of —NR³²— is selected fromhydrogen and C₁₋₁₀ alkyl. In some embodimens, R⁴ is selected from

In some embodiments, R³² of —NR³²— is hydrogen. In some embodiments, R³²of —NR³²— is selected from C₁₋₁₀ alkyl.

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R⁵¹ is independentlyselected at each occurrence from —((CH₂)_(q)—CH₂-D)_(z)-T and optionallysubstituted C₅₋₃₀ alkyl; wherein q is independently selected at at eachoccurrence from 1 to 6, each D is independently selected from —O—,—NR³²—, —S—, or —SO₂—; each z is selected from 1-20; and each T isselected from hydrogen and optionally substituted —C₁-C₆ alkyl.

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R⁵¹ is independentlyselected at each occurrence from —((CH₂)_(q)—CH₂-D)_(z)-T and optionallysubstituted C₅₋₃₀ alkyl; wherein q is independently selected at at eachoccurrence from 1 to 6, each D is independently selected from —O—,—NR³²—, —S—, or —SO₂—; each z is selected from 3-20; and each T isselected from hydrogen and optionally substituted —C₁-C₆ alkyl. In someembodiments, R⁵¹ is optionally substituted C₅₋₃₀ alkyl. In someembodiments, R⁵¹ is selected C₅₋₃₀ alkyl, is selected from optionallysubstituted C₅₋₂₅ alkyl, optionally substituted C₅₋₂₀ alkyl, optionallysubstituted C₅₋₁₅ alkyl, and optionally substituted C₅₋₁₀ alkyl. In someembodiments, R⁵¹ is optionally substituted C₅₋₁₀ alkyl. In someembodiments, the C₅₋₃₀ alkyl is optionally substituted with one or moresubstituents selected from halogen, —OR³⁰, —N(R³⁰)₂,—(O—CH₂—(CH₂)_(p))_(n)—W, —C(O)R³⁰, —C(O)N(R³⁰)₂, —N(R³⁰)C(O)R³⁰,—C(O)OR³⁰, —OC(O)R³⁰, —S(O)R³⁰, —S(O)₂R³⁰, —P(O)(OR³⁰)₂, —OP(O)(OR³⁰)₂,—NO₂, ═O, ═S, ═N(R³⁰), and —CN. In some embodiments, the C₅₋₃₀ alkyl isoptionally substituted with one or more substituents selected from—OR³⁰, —N(R³⁰)₂, —C(O)R³⁰, —C(O)N(R³⁰)₂, —N(R³⁰)C(O)R³⁰, —C(O)OR³⁰,—OC(O)R³⁰, —S(O)R³⁰, —S(O)₂R³⁰, —NO₂, and —CN. In some embodiments, theC₅₋₃₀ alkyl is optionally substituted with one or more substituentsselected from —OR³⁰. In some embodiments, each R³⁰ is independentlyselected at each occurrence from hydrogen and C₁₋₁₀ alkyl. In someembodiments, R³⁰ of —OR³⁰ is independently selected from hydrogen andC₁₋₁₀ alkyl. In some embodiments, R³⁰ of —OR³⁰ is independently selectedfrom C₁₋₁₀ alkyl.

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R⁵¹, is selected from aC₃₋₈ carbocycle. In some embodiments, R⁵¹, is a C₃₋₆ carbocycle. In someembodiments, R⁵¹, is selected from a C₃₋₆ cycloalkyl.

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R⁴ is

wherein R¹⁰⁰ is hydrogen or C₁₋₁₀ alkyl; and R¹¹⁰ is selected from—S(O)₂R⁵¹; or R¹⁰⁰ and R¹¹⁰ together with the nitrogen to which they arebound form a 3-10-membered heterocycle optionally substituted with oneor more substituents selected from: hydroxy, halogen, —CN, —NO₂, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, and C₁-C₆ alkoxy, and ═O.

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R¹⁰⁰ and R¹¹⁰ are eachfurther independently selected from —SR³¹, —N(R³¹)₂, —C(O)R³¹,—C(O)N(R³¹)₂, —N(R³¹)C(O)R³¹, —C(O)OR³¹, —OC(O)R³¹, —S(O)R³¹, —S(O)₂R³¹,—P(O)(OR³¹)₂, —OP(O)(OR³¹)₂, —NO₂, —CN, optionally substituted C₃₋₂₀carbocycle and optionally substituted 3- to 20-membered heterocycle,when R¹ is not hydroxy. In some embodiments, for the compound or salt ofFormula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R¹⁰⁰ and R¹¹⁰are each further independently selected from —S(O)R³¹, —S(O)₂R³¹, —NO₂,—CN, optionally substituted C₃₋₂₀ carbocycle and optionally substituted3- to 20-membered heterocycle, when R¹ is not hydroxy. In someembodiments, R¹⁰⁰ and R¹¹⁰ are each further independently selected from—S(O)R³¹ and —S(O)₂R³¹, when R¹ is not hydroxy. In some embodiments,each R³¹ is independently selected at each occurrence from hydrogen; andC₁₋₁₀ alkyl, wherein the C₁₋₁₀ alkyl is optionally substituted with oneor more substituents independently selected from halogen, —OH, —CN,—NO₂, —NH₂, ═O, ═S, C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl, and —O—C₁₋₁₀ alkyl.In some emobidments, the C₁₋₁₀ alkyl is optionally substituted with oneor more substituents independently selected from —O—C₁₋₁₀ alkyl.

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R⁴ is

In some embodiments, R¹²⁰ of R⁴ is selected from: hydrogen,—(CH₂—CH₂-G)_(y)-V; and C₃₋₁₀ alkyl optionally substituted with one ormore substituents independently selected from halogen, —OR³¹, —SR³¹,—N(R³¹)₂, —C(O)R³¹, —C(O)N(R³¹)₂, —N(R³¹)C(O)R³¹, —C(O)OR³¹, —OC(O)R³¹,—NO₂, —CN, C₃₋₂₀ carbocycle, and 3- to 20-membered heterocycle; andC₃₋₂₀ saturated carbocycle and 3- to 20-membered heterocycle each ofwhich is optionally substituted with one or more substituentsindependently selected from halogen, —OR³¹, —SR³¹, —N(R³¹)₂, —C(O)R³¹,—C(O)N(R³¹)₂, —N(R³¹)C(O)R³¹, —C(O)OR³¹, —OC(O)R³¹, —NO₂, ═O, ═S,═N(R³¹), —CN, C₁₋₆ alkyl, C₁₋₆ alkyl-R³¹, C₂₋₆ alkenyl, and C₂₋₆alkynyl.

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R⁴ is

and R¹²⁰ of R⁴ is hydrogen.

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R⁴ is

and R¹²⁰ of R⁴ is —(CH₂—CH₂-G)_(y)-V.

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R⁴ is

and R¹²⁰ of R⁴ is C₃₋₁₀ alkyl optionally substituted with one or moresubstituents independently selected from halogen, —OR³¹, —SR³¹,—N(R³¹)₂, —C(O)R³¹, —C(O)N(R³¹)₂, —N(R³¹)C(O)R³¹, —C(O)OR³¹, —OC(O)R³¹,—NO₂, —CN, C₃₋₂₀ carbocycle, and 3- to 20-membered heterocycle. In someembodiments, R¹²⁰ of R⁴ is C₃₋₁₀ alkyl, optionally substituted with oneor more substituents independently selected from —OR³¹, —SR³¹, and—N(R³¹)₂, wherein each R³¹ is independently selected from hydrogen, andC₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocycle, and 3- to10-membered heterocycle.

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R⁴ is

and R¹²⁰ of R⁴ is C₁₋₂ alkyl substituted with one or more substituentsindependently selected from halogen, —OR³¹, —N(R³¹)₂, —C(O)R³¹,—C(O)N(R³¹)₂, —N(R³¹)C(O)R³¹, —C(O)OR³¹, —OC(O)R³¹, —S(O)R³¹, —S(O)₂R³¹,—P(O)(OR³¹)₂, —OP(O)(OR³¹)₂, —NO₂, —CN, C₃₋₂₀ carbocycle and 3- to20-membered heterocycle.

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), for the compound or salt ofFormula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R⁴ is

and R¹²⁰ is selected from —(CH₂—CH₂-G)_(y)-V, wherein y of—(CH₂—CH₂-G)_(y)-V for R¹²⁰ is 1 to 1000. In some embodiments, y is 1 to800. In some embodiments, y is 1 to 500. In some embodiments, y is 1 to300. In some embodiments, y is 1 to 100. In some embodiments, y is 1 to50. In some embodiments, y is 1 to 25. In some embodiments, y is 3 to1000. In some embodiments, y is 10 to 1000. In some embodiments, y is 50to 1000. In some embodiments, y is 100 to 1000. In some embodiments, yis 200 to 1000. In some embodiments, y is 500 to 1000. In someembodiments, y of —(CH₂—CH₂-G)_(y)-V for R¹²⁰ is 3 to 10. In someembodiments, y of —(CH₂—CH₂-G)_(y)-V for R¹²⁰ is 5 to 10. In someembodiments, y is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 25, or 100.

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R² is selected fromhydrogen and an optionally substituted C₁-C₆ alkoxy, whereinsubstituents are independently selected at each occurrence from hydroxy,halogen, —CN, —NO₂, and C₁-C₆ alkoxy. In some embodiments, R² isselected from hydrogen and an optionally substituted C₁-C₆ alkoxy,wherein substituents are independently selected at each occurrence fromhydroxy, halogen, —NO₂, and C₁-C₆ alkoxy.

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R² is selected fromhydrogen and C₁-C₆ alkoxy. In some embodiments, R² is selected fromhydrogen and —OMe. In some embodiments, R² is —OMe.

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R³ is selected fromhydrogen and an optionally substituted C₁-C₆ alkoxy, wherein thesubstituents are independently selected at each occurrence from hydroxyand C₁-C₆ alkoxy. In some embodiments, R³ is selected from hydrogen andC₁-C₆ alkoxy.

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R³ is selected from C₁-C₆alkoxy. In some embodiments, R³ is —OMe.

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R⁵ is selected fromhydrogen, hydroxy, and an optionally substituted C₁-C₆ alkoxy, whereinsubstituents are independently selected at each occurrence from hydroxy,halogen, —CN, —NO₂, and C₁-C₆ alkoxy.

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R⁵ is, hydroxy.

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R⁶ and R⁷ are eachindependently selected from hydrogen and hydroxy. In some embodiments,R⁶ and R⁷ are each hydrogen. In some embodiments, R⁶ is hydrogen and R⁷hydroxy. In some embodiments, R⁶ and R⁷ come together to form

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R¹ is selected from

and optionally substituted 3- to 10-membered heterocycle. In someembodiments, for the compound or salt of Formula (I), (IA), (IB), (IC),(ID), (IE), (IF), or (IG), R¹ is selected from

In some embodiments, for the compound or salt of Formula (I), (IA),(IB), (IC), (ID), (IE), (IF), or (IG), R¹ is selected from hydroxy.

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R¹ is selected from

optionally substituted C₃₋₁₀ carbocycle and optionally substituted 3- to10-membered heterocycle.

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R¹ is selected from

and optionally substituted 3- to 10-membered heterocycle.

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R¹ is selected from —OH.

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R¹ is selected from: —OH,

optionally substituted 3- to 10-membered heterocycle, and optionallysubstituted C₃₋₁₀ carbocycle.

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R¹ is selected from: —OH,

and optionally substituted 3- to 10-membered heterocycle.

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R¹ is an optionallysubstituted 3- to 10-membered heterocycle. In some embodiments, theoptionally substituted heterocycle is 3-, 4-, 5-, 6-, 7-, 8-, 9-, or a10-membered heterocycle. In some embodiments, the optionally substituted3- to 10-membered heterocycle is a 3- or 4-membered heterocycle, a 5- or6-membered heterocycle, a 7- or 8-membered heterocycle, or a 9- or10-membered heterocycle.

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R¹ is an optionallysubstituted 5- to 6-membered heterocycle comprising at least 1heteroatom that is selected from oxygen, nitrogen, sulfur, boron,phoshprous, silicon, selenium, and any combination thereof. In someembodiments, the optionally substituted 5- to 6-membered heterocyclecomprises at least 1 heteroatom that is selected from oxygen, nitrogen,sulfur, and any combination thereof.

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), the optionally substituted5- to 6-membered heterocycle of R¹ comprises at least 1 nitrogen. Insome embodiments, the optionally substituted 5- to 6-memberedheterocycle of R¹ is selected from

any of which is optionally substituted with one or more substituentsindependently selected from: hydroxy, halogen, —CN, —NO₂, ═O, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, 3- to10-membered heterocycle, and C₃₋₁₀ carbocycle, wherein the 3- to10-membered heterocycle and C₃₋₁₀ carbocycle are each optionallysubstituted with one or more substituents independently selected fromhydroxy, halogen, —CN, —NO₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆hydroxyalkyl, and C₁-C₆ alkoxy. In some embodiments, the one or moresubstituents are independently selected from hydroxy, ═O, C₁-C₆ alkyl,3- to 8-membered heterocycle, and C₃₋₈ carbocycle, wherein the 3- to8-membered heterocycle and C₃₋₈ carbocycle are each optionallysubstituted with one or more substituents independently selected fromhydroxy, halogen, —CN, —NO₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆hydroxyalkyl, and C₁-C₆ alkoxy.

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R¹ is

In some embodiments, for the compound or salt of Formula (I), (IA),(IB), (IC), (ID), (IE), (IF), or (IG), R²² of R¹ is selected fromoptionally substituted C₁-C₆ alkyl, and —P(═O)(R²⁴)₂.

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R²² of R¹ is hydrogen.

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R²² of R¹ is —P(═O)(R²⁴)₂,and R²⁴ is selected from optionally substituted C₁₋₁₀ alkyl. In someembodiments, R¹ is

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R²² of R¹ is C₁-C₆ alkyloptionally substituted with one or more substituents selected from—N(R³⁰)₂, —(O—CH₂—(CH₂)_(p))_(n)—W, —OR³⁰, optionally substituted C₃₋₁₀carbocycle, and optionally substituted 3- to 10-membered heterocycle,and R³⁰ is selected from hydrogen and optionally substituted C₁₋₁₀alkyl. In some embodiments, R²² of R¹, is C₁-C₆ alkyl substituted withone or more substituents selected from —N(R³⁰)₂,—(O—CH₂—(CH₂)_(p))_(n)—W, and —OR³⁰.

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R²² of R¹ is C₁-C₆ alkylsubstituted with one or more substituents selected from —N(R³⁰)₂. Insome embodiments, R¹ is

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R²² of R¹ is C₁-C₆ alkylsubstituted with one or more substituents selected from—(O—CH₂—(CH₂)_(p))_(n)—W, wherein n is 1 to 1000. In some embodiments, nis 1 to 800. In some embodiments, n is 1 to 500. In some embodiments, nis 1 to 300. In some embodiments, n is 1 to 100. In some embodiments, nis 1 to 50. In some embodiments, n is 1 to 25. In some embodiments, n is3 to 1000. In some embodiments, n is 10 to 1000. In some embodiments, nis 50 to 1000. In some embodiments, n is 100 to 1000. In someembodiments, n is 200 to 1000. In some embodiments, n is 500 to 1000. Insome embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20, 25, or 100. In some embodiments, p is 1 to 1000.In some embodiments, p is 1 to 800. In some embodiments, p is 1 to 500.In some embodiments, p is 1 to 300. In some embodiments, p is 1 to 100.In some embodiments, p is 1 to 50. In some embodiments, p is 1 to 25. Insome embodiments, p is 3 to 1000. In some embodiments, p is 10 to 1000.In some embodiments, p is 50 to 1000. In some embodiments, p is 100 to1000. In some embodiments, p is 200 to 1000. In some embodiments, p is500 to 1000. In some embodiments, p is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, or 100.

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R²² of R¹ is C₁-C₆ alkylsubstituted with one or more substituents selected from—(O—CH₂—(CH₂)_(p))_(n)—W, and —OR³⁰. In some embodiments, R¹ is selectedfrom:

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R²² of R¹ is C₁-C₆ alkylsubstituted with substituents selected from an optionally substitutedC₃₋₁₀ carbocycle. In some embodiments, the optionally substituted C₃₋₁₀carbocycle is selected from a C₃₋₆ carbocycle. In certain embodiments,the C₃₋₆ carbocycle is unsaturated. In certain embodiments, the C₃₋₆carbocycle is saturated. In some embodiments, the optionally substitutedC₃₋₆ carbocycle is selected from

In some embodiments, R²² of R¹ is C₁-C₆ alkyl substituted with phenyl.In some embodiments, R¹ is selected from:

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R²² of R¹ is C₁-C₆ alkylsubstituted with one or more substituents selected from an optionallysubstituted 3- to 6-membered heterocycle. In some embodiments, theoptionally substituted 3- to 6-membered heterocycle comprises at leastone heteroatom selected from N, O, S, and any combination thereof.

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R²² is C₁-C₆ alkylsubstituted with one or more substituents selected from optionallysubstituted 3- to 8-membered heterocycle. In some embodiments, R²² isC₂-C₃ alkyl substituted with one or more substituents selected fromoptionally substituted 3- to 8-membered heterocycle. In someembodiments, R²² of R¹ is C₁-C₆ alkyl substituted with one or moresubstituents selected from an optionally substituted 3- to 8-memberedheterocycle wherein the optionally substituted 3- to 8-memberedheterocycle comprises at least one heteroatom selected from N and O. Insome embodiments, the 3- to 8-membered heterocycle of R²² is saturated.In some embodiments, the 3- to 8-membered heterocycle of R²² issubstituted with one or more substituents selected from —S(O)₂R³⁰, C₁₋₆alkyl and —OR³⁰. In some embodiments, R³⁰ of —S(O)₂R³⁰ is selected fromC₁₋₁₀ alkyl and R³⁰ of —OR³⁰ is selected from hydrogen and C₁₋₆ alkyl.In some embodiments, R²² of R¹ is C₁-C₆ alkyl substituted with one ormore substituents selected from an optionally substituted 3- to6-membered heterocycle wherein the optionally substituted 3- to6-membered heterocycle comprises at least one heteroatom selected from Nand O. In some embodiments, the 3- to 6-membered heterocycle issubstituted with one or more substituents selected from optionallysubstituted C₁₋₆ alkyl and —OR³⁰. In some embodiments, R¹ is selectedfrom:

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R¹ is selected from:

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R¹ is selected from:

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R¹ is

In some embodiments, R²⁰ of R¹ is selected from hydrogen and optionallysubstituted C₁-C₃ alkyl. In some embodiments, R²¹ of R¹ is selected fromhydrogen and optionally substituted C₁-C₃ alkyl. In some embodiments,R²¹ of R¹ is an optionally substituted C₁₋₁₀ alkyl. In some embodiments,R²¹ of R¹ is C₁₋₁₀ alkyl substituted with one or more substituentsselected from —OR³⁰, —N(R³⁰)₂, —(O—CH₂—(CH₂)_(p))_(n)—W, optionallysubstituted C₃₋₁₀ carbocycle and optionally substituted 3- to10-membered heterocycle. In some embodiments, R¹ is selected from:

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R¹ is

wherein R²¹ of R¹ is an optionally substituted 3- to 7-memberedheterocycle. In some embodiments, the 3- to 7-membered heterocycle issubstituted with one or more substituents selected from —OR³⁰ andoptionally substituted C₁₋₁₀ alkyl. In some embodiments, R¹ is selectedfrom:

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R¹ is

In some embodiments, R²³ of R¹ is an optionally substituted C₁-C₆ alkyl.In some embodiments, C₁-C₆ alkyl is substituted with one or moresubstituents selected from —OR³⁰, —N(R³⁰)₂, optionally substituted C₁₋₁₀alkyl, optionally substituted C₃₋₁₀ carbocycle and 3- to 10-memberedheterocycle. In some embodiments, R¹ is selected from:

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R²³ of R¹ is an optionallysubstituted 3- to 7-membered heterocycle. In some embodiments, the 3- to7-membered heterocycle is substituted with one or more substituentsselected from optionally substituted C₁₋₁₀ alkyl. In some embodiments,R¹ is selected from:

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R¹ is selected from:

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R¹ is selected from:

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R¹ is selected from:

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R¹ is selected from:

In some embodiments, for the compound or salt of Formula (I), (IA),(IB), (IC), (ID), (IE), (IF), or (IG), R¹ is selected from:

In some embodiments, for the compound or salt of Formula (I), (IA),(IB), (IC), (ID), (IE), (IF), or (IG):

R¹ is selected from

R² is selected from hydrogen and an optionally substituted C₁-C₆ alkoxy,such as R² is a C₁-C₆ alkoxy group, and preferably R² is —OCH₃;

R³ is selected from an optionally substituted C₁-C₆ alkoxy group, suchas R³ is a C₁-C₆ alkoxy group, and preferably R³ is —OCH₃;

R^(4′) is selected from

R⁵ is selected from hydroxy, and an optionally substituted C₁-C₆ alkoxy,such as R⁵ is a C₁-C₆ alkoxy group, and preferably R⁵ is hydroxy;

R⁶ and R⁷ come together to form

R²² is selected from C₁-C₆ alkyl, such as R²² is a C₂-C₄ alkyl, whereinthe C₁-C₆ alkyl or C₂-C₄ alkyl is substituted with an optionallysubstituted saturated 3- to 8-membered heterocycle, oxo, —O—C₁₋₁₀ alkyl,—NR³⁰—S(O)₂R³⁰, —SO₂—N(R³⁰)₂, or —S(O)₂R³⁰, wherein the substitutents onthe 3- to 8-membered saturated heterocycle of R²² are independentlyselected from —NR⁵²—SO₂—R³⁰, —SO₂—N(R⁵²)₂, —S(O)₂R³⁰, C₁₋₆ alkyl, C₁₋₆hydroxyalkyl, and —OR³⁰, and wherein R³⁰ of —S(O)₂R³⁰ is selected fromC₁₋₁₀ alkyl and R³⁰ of —OR³⁰ is selected from hydrogen and C₁₋₆ alkyl;

R¹⁰⁰ is selected from hydrogen and C₁₋₁₀ alkyl;

R^(110′) is selected from —S(O)₂R^(51′), wherein R^(51′) is selectedfrom substituted C₁₋₄ alkyl, —((CH₂)_(q)—CH₂-D)_(z)-T, optionallysubstituted C₁₋₃₀ alkyl, optionally substituted C₃₋₈ carbocyle, andoptionally substituted 3-10 membered heterocycle;

R⁵² is selected from hydrogen and C₁₋₁₀ alkyl;

R³⁰ is independently selected at each occurrence from hydrogen; C₁₋₁₀alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocycle, and 3- to10-membered heterocycle, each of which is optionally substituted withone or more substituents independently selected from halogen, —OH, —CN,—NO₂, —NH₂, ═O, ═S, C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl, —O—C₁₋₁₀ alkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocycle, and 3- to 10-memberedheterocycle;

q is selected from 1 to 6;

each z is selected from 1-20; and

each T is selected from hydrogen and optionally substituted —C₁-C₆alkyl.

In some embodiments, for the compound or salt of Formula (I), (IA),(IB), (IC), (ID), (IE), (IF), or (IG): R^(51′) is independently selectedat each occurrence from —((CH₂)_(q)—CH₂-D)_(z)-T, optionally substitutedC₁₋₃₀ alkyl, optionally substituted C₃₋₈ carbocyle, and optionallysubstituted 3-10 membered heterocycle. In some embodiments, R^(51′) isindependently selected at each occurrence from —((CH₂)_(q)—CH₂-D)_(z)-T,optionally substituted C₃₋₈ carbocyle, and optionally substituted 3-10membered heterocycle. In some embodiments, R^(51′) is independentlyselected at each occurrence from —((CH₂)_(q)—CH₂-D)_(z)-T, C₃₋₈carbocyle, and 3-10 membered heterocycle.

In some embodiments, for the compound or salt of Formula (I), (IA),(IB), (IC), (ID), (IE), (IF), or (IG): R^(51′) is selected from—((CH₂)_(q)—CH₂-D)_(z)-T. In some embodiments, R^(51′) is selected fromC₁₋₃₀ alkyl. In some embodiments, R^(51′) is selected fromunsubsustituted C₁₋₃₀ alkyl. In some embodiments, R^(51′) is selectedfrom C₃₋₈ carbocyle. In some embodiments, R^(51′) is selected fromunsubstituted C₃₋₆ carbocyle. In some embodiments, R^(51′) is selectedfrom C₃₋₅ carbocyle. In some embodiments, R^(51′) is selected from 3-6membered heterocycle. In some embodiments, R^(51′) is selected fromunsubstituted 3-6 membered heterocycle. In some embodiments, q isselected from 1 to 6. In som embodiments, each D is independentlyselected from —O—. In some embodiments, z is selected from 1-10. In someembodiments, T is selected from hydrogen and C₁-C₆ alkyl. In someembodiments, the optional substituents of R^(51′) on optionallysubstituted C₁₋₃₀ alkyl, optionally substituted C₃₋₈ carbocyle, andoptionally substituted 3-10 membered heterocycle are independentlyselected at each occurrence from:

-   -   halogen, —OR^(30′), —N(R^(30′))₂, —(O—CH₂—(CH₂)_(p))_(n)—W,        —SR^(30′), —C(O)R^(30′), —C(O)N(R^(30′))₂,        —N(R^(30′))C(O)R^(30′), —C(O)OR^(30′), —OC(O)R^(30′),        —S(O)R^(30′), —S(O)₂R^(30′), —P(O)(OR^(30′))₂,        —OP(O)(OR^(30′))₂, —NO₂, ═O, ═S, ═N(R^(30′)), and —CN;    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, each of which is        optionally substituted with one or more substituents        independently selected from halogen, —OR^(30′), —SR^(30′),        —N(R^(30′))₂, —C(O)R^(30′), —C(O)N(R^(30′))₂,        —N(R^(30′))C(O)R^(30′), —C(O)OR^(30′), —OC(O)R^(30′),        —S(O)R^(30′), —S(O)₂R^(30′), —P(O)(OR^(30′))₂,        —OP(O)(OR^(30′))₂, —NO₂, ═O, ═S, ═N(R^(30′)), —CN, C₃₋₁₀        carbocycle and 3- to 10-membered heterocycle; and    -   C₃₋₁₀ carbocycle and 3- to 10-membered heterocycle each of which        is optionally substituted with one or more substituents        independently selected from halogen, —OR^(30′), —SR^(30′),        —N(R^(30′))₂, —C(O)R^(30′), —C(O)N(R^(30′))₂,        —N(R^(30′))C(O)R^(30′), —C(O)OR^(30′), —OC(O)R^(30′),        —S(O)R^(30′), —S(O)₂R^(30′), —P(O)(OR^(30′))₂,        —OP(O)(OR^(30′))₂, —NO₂, ═O, ═S, ═N(R^(30′)), —CN, C₁₋₆ alkyl,        C₁₋₆ alkyl-R^(30′), C₂₋₆ alkenyl, and C₂₋₆ alkynyl.        In some embodiments, R^(30′) of R^(51′) is independently        selected at each occurrence from hydrogen; C₁₋₁₀ alkyl, C₂₋₁₀        alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocycle, and 3- to 10-membered        heterocycle, each of which is optionally substituted with one or        more substituents independently selected from halogen, —OH, —CN,        —NO₂, —NH₂, ═O, ═S, C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl, —O—C₁₋₁₀        alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocycle, and 3- to        10-membered heterocycle.

In some embodiments, for the compound or salt of Formula (I), (IA),(IB), (IC), (ID), (IE), (IF), or (IG);

-   R¹ is selected from: —OH, and

-   R² is selected from hydrogen and an optionally substituted C₁-C₆    alkoxy, wherein substituents are independently selected at each    occurrence from hydroxy , halogen, —CN, —NO₂, C₁-C₆ alkoxy, 3- to    10-membered heterocycle, and C₃₋₁₀ carbocycle, wherein the 3- to    10-membered heterocycle and C₃₋₁₀ carbocycle are each optionally    substituted with one or more substituents independently selected    from hydroxy, halogen, —CN, —NO₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl,    C₁-C₆ hydroxyalkyl, and C₁-C₆ alkoxy; R³ is selected from hydrogen    and an optionally substituted C₁-C₆ alkoxy, wherein the substituents    are independently selected at each occurrence from hydroxy, halogen,    —CN, —NO₂, C₁-C₆ alkoxy, 3- to 10-membered heterocycle, and C₃₋₁₀    carbocycle, wherein the 3- to 10-membered heterocycle and C₃₋₁₀    carbocycle, are each optionally substituted with one or more    substituents independently selected from hydroxy, halogen, —CN,    —NO₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, and C₁-C₆    alkoxy; and-   R^(4′) is selected from,

-   R⁵ is selected from hydrogen, hydroxy, and an optionally substituted    C₁-C₆ alkoxy, wherein substituents are independently selected at    each occurrence from hydroxy, halogen, —CN, —NO₂, C₁-C₆ alkoxy, 3-    to 10-membered heterocycle, and C₃₋₁₀ carbocycle, wherein the 3- to    10-membered heterocycle, and C₃₋₁₀ carbocycle are each optionally    substituted with one or more substituents independently selected    from hydroxy, halogen, —CN, —NO₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl,    C₁-C₆ hydroxyalkyl, and C₁-C₆ alkoxy;-   R⁶ and R⁷ come together to form

-   R²² is selected from optionally substituted C₁-C₆ alkyl, optionally    substituted 3- to 10-membered heterocycle, and optionally    substituted C₃₋₁₀ carbocycle, and —P(═O)(R²⁴)₂;-   R¹⁰⁰ is selected from:    -   hydrogen and —(CH₂—CH₂-G)_(y)-V; and    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, wherein each of which        is optionally substituted with one or more substituents        independently selected from halogen, —OR³¹, —SR³¹, —N(R³¹)₂,        —C(O)R³¹, —C(O)N(R³¹)₂, —N(R³¹)C(O)R³¹, —C(O)OR³¹, —OC(O)R³¹,        —S(O)R³¹, —S(O)₂R³¹, —P(O)(OR³¹)₂, —OP(O)(OR³¹)₂, —NO₂, —CN,        C₃₋₂₀ carbocycle and 3- to 20-membered heterocycle; and    -   C₃₋₂₀ carbocycle and 3- to 20-membered heterocycle each of which        is optionally substituted with one or more substituents        independently selected from halogen, —OR³¹, —SR³¹, —N(R³¹)₂,        —C(O)R³¹, —C(O)N(R³¹)₂, —N(R³¹)C(O)R³¹, —C(O)OR³¹, —OC(O)R³¹,        —S(O)R³¹, —S(O)₂R³¹, —P(O)(OR³¹)₂, —OP(O)(OR³¹)₂, —NO₂, ═O, ═S,        ═N(R³¹), —CN, C₁₋₆ alkyl, C₁₋₆ alkyl-R³¹, C₂₋₆ alkenyl, and C₂₋₆        alkynyl;-   R^(110′) is selected from:    -   hydrogen, —(CH₂—CH₂-G)_(y)-V, —S(O)R^(51′), —S(O)₂R^(51′),        —C(O)R^(51′), —C(O)N(R^(51′))₂, and —C(O)OR^(51′); and    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, wherein each of which        is optionally substituted with one or more substituents        independently selected from halogen, —OR³¹, —SR³¹, —N(R³¹)₂,        —C(O)R³¹, —C(O)N(R³¹)₂, —N(R³¹)C(O)R³¹, —C(O)OR³¹, —OC(O)R³¹,        —S(O)R³¹, —S(O)₂R³¹, —P(O)(OR³¹)₂, —OP(O)(OR³¹)₂, —NO₂, —CN,        C₃₋₂₀ carbocycle and 3- to 20-membered heterocycle; and    -   C₃₋₂₀ carbocycle and 3- to 20-membered heterocycle each of which        is optionally substituted with one or more substituents        independently selected from halogen, —OR³¹, —SR³¹, —N(R³¹)₂,        —C(O)R³¹, —C(O)N(R³¹)₂, —N(R³¹)C(O)R³¹, —C(O)OR³¹, —OC(O)R³¹,        —S(O)R³¹, —S(O)₂R³¹, —P(O)(OR³¹)₂, —OP(O)(OR³¹)₂, —NO₂, ═O, ═S,        ═N(R³¹), —CN, C₁₋₆ alkyl, C₁₋₆ alkyl-R³¹, C₂₋₆ alkenyl, and C₂₋₆        alkynyl; or-   R¹⁰⁰ and R^(110′) together with the nitrogen to which they are bound    form a 3-10-membered heterocycle optionally substituted with one or    more substituents independently selected from: hydroxy, halogen,    —CN, —NO₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, and    C₁-C₆ alkoxy, wherein when R¹ is hydroxy, the ring formed by R¹⁰⁰    and R¹¹⁰ is not unsubstituted morpholine-   each G is independently selected from —O—, —NR³²—, —S—, or —SO₂—;-   each D is independently selected from —O—, —NR³²—, —S—, or —SO₂—;-   each y is selected from 3-20;-   each z is selected from 1-20;-   each V is selected from hydrogen and optionally substituted —C₁-C₆    alkyl;-   each T is selected from hydrogen and optionally substituted —C₁-C₆    alkyl;-   each R³¹ is independently selected from hydrogen, and C₁₋₁₀ alkyl,    C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocycle, and 3- to    10-membered heterocycle, each of which is optionally substituted    with one or more substituents independently selected from halogen,    —OH, —CN, —NO₂, —NH₂, ═O, ═S, C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl,    —O—C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocycle, and    3- to 10-membered heterocycle; and-   R³² is independently selected at each occurrence from: hydrogen; and    C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocycle, and 3-    to 10-membered heterocycle, each of which is optionally substituted    with one or more substituents independently selected from halogen,    —OH, —CN, —NO₂, —NH₂, ═O, ═S, C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl,    —O—C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocycle, and    3- to 10-membered heterocycle;-   wherein the optional substituents on R²², R⁵¹, V, and T are    independently selected at each occurrence from:    -   halogen, —OR³⁰, —N(R³⁰)₂, —(O—CH₂—(CH₂)_(p))_(n)—W, —SR³⁰,        —C(O)R³⁰, —C(O)N(R³⁰)₂, —N(R³⁰)C(O)R³⁰, —C(O)OR³⁰, —OC(O)R³⁰,        —S(O)R³⁰, —S(O)₂R³⁰, —P(O)(OR³⁰)₂, —OP(O)(OR³⁰)₂, —NO₂, ═O, ═S,        ═N(R³⁰), and —CN;    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, each of which is        optionally substituted with one or more substituents        independently selected from halogen, —OR³⁰, —SR³⁰, —N(R³⁰)₂,        —C(O)R³⁰, —C(O)N(R³⁰)₂, —N(R³⁰)C(O)R³⁰, —C(O)OR³⁰, —OC(O)R³⁰,        —S(O)R³⁰, —S(O)₂R³⁰, —P(O)(OR³⁰)₂, —OP(O)(OR³⁰)₂, —NO₂, ═O, ═S,        ═N(R³⁰), —CN, C₃₋₁₀ carbocycle and 3- to 10-membered        heterocycle; and    -   C₃₋₁₀ carbocycle and 3- to 10-membered heterocycle each of which        is optionally substituted with one or more substituents        independently selected from halogen, —OR³⁰, —SR³⁰, —N(R³⁰)₂,        —C(O)R³⁰, —C(O)N(R³⁰)₂, —N(R³⁰)C(O)R³⁰, —C(O)OR³⁰, —OC(O)R³⁰,        —S(O)R³⁰, —S(O)₂R³⁰, —P(O)(OR³⁰)₂, —OP(O)(OR³⁰)₂, —NO₂, ═O, ═S,        ═N(R³⁰), —CN, C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;-   R³⁰ is independently selected at each occurrence from hydrogen;    C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocycle, and 3-    to 10-membered heterocycle, each of which is optionally substituted    with one or more substituents independently selected from halogen,    —OH, —CN, —NO₂, —NH₂, ═O, ═S, C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl,    —O—C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocycle, and    3- to 10-membered heterocycle;-   R^(51′) is independently selected at each occurrence from optionally    substituted C₃₋₈ carbocycle, optionally substituted 3-10 membered    heterocycle, —((CH₂)_(q)—CH₂-D)_(z)-T and optionally substituted    C₅₋₃₀ alkyl; wherein C₃₋₁₀ carbocycle and 3- to 10-membered    heterocycle each of which is optionally substituted with one or more    substituents independently selected from halogen, —OR³⁰, —SR³⁰,    —N(R³⁰)₂, —C(O)R³⁰, —C(O)N(R³⁰)₂, —N(R³⁰)C(O)R³⁰, —C(O)OR³⁰,    —OC(O)R³⁰, —S(O)R³⁰, —S(O)₂R³⁰, —P(O)(OR³⁰)₂, —OP(O)(OR³⁰)₂, —NO₂,    ═O, ═S, ═N(R³⁰), —CN, C₁₋₆ alkoxy, C₁₋₆ alkyl, C₂₋₆ alkenyl, and    C₂₋₆ alkynyl;-   q is selected from 1 to 6;-   each p is selected from 1 or 2;-   each n is selected from 3-7; and-   each W is selected from hydrogen, —OH, —C₁-C₄ alkyl and —O(C₁-C₄    alkyl).

In some embodiments, for the compound or salt of Formula (I), (IA),(IB), (IC), (ID), (IE), (IF), or (IG),

-   R¹ is selected from

-   R²² is selected from optionally substituted C₁-C₆ alkyl;-   wherein the substituents on R²², is independently selected at each    occurrence from: —S(O)R³⁰, and —S(O)₂R³⁰, preferably —S(O)₂R³⁰ ;-   R² is selected from hydrogen and an optionally substituted C₁-C₆    alkoxy;-   R³ is selected from hydrogen and an optionally substituted C₁-C₆    alkoxy;-   R^(4′) is selected from

-   R⁵ is selected from hydrogen, hydroxy, and an optionally substituted    C₁-C₆ alkoxy;-   R⁶ and R⁷ are each independently selected from hydrogen, hydroxy,    and C₁-C₆ alkoxy; or R⁶ and R⁷ come together to form

-   preferably R⁶ and R⁷ come together to form

-   R¹⁰⁰ is selected from:    -   hydrogen and    -   C₁₋₁₀ alkyl;-   R^(110′) is selected from:    -   —S(O)R^(51′) and —S(O)₂R^(51′), preferably S(O)₂R^(51′);-   R^(51′) is independently selected at each occurrence from    substituted C₁₋₄ alkyl, optionally substituted C₃₋₈ carbocycle,    optionally substituted 3-10 membered heterocycle,    —((CH₂)_(q)—CH₂-D)_(z)-T and optionally substituted C₅₋₃₀ alkyl;-   wherein the substituents on R^(51′), and T are independently    selected at each occurrence from:    -   halogen, —OR³⁰, —N(R³⁰)₂, —SR³⁰, —C(O)R³⁰, —C(O)N(R³⁰)₂,        —N(R³⁰)C(O)R³⁰, —C(O)OR³⁰, —OC(O)R³⁰, —S(O)R³⁰, —S(O)₂R³⁰,        —P(O)(OR³⁰)₂, —OP(O)(OR³⁰)₂, —NO₂, ═O, ═S, ═N(R³⁰), and —CN;-   R³⁰ is independently selected at each occurrence from hydrogen;    C₁₋₁₀ alkyl, C₃₋₆ carbocycle, and 3- to 6-membered heterocycle, each    of which is optionally substituted with one or more substituents    independently selected from halogen, —OH, —CN, —NO₂, —NH₂, ═O, ═S,    C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl, —O—C₁₋₁₀ alkyl, C₃₋₆ carbocycle, and    3- to 6-membered heterocycle;-   each D is independently selected from —O—;-   q is selected from 1 to 6;-   each z is selected from 1-20;-   each T is selected from hydrogen and optionally substituted —C₁-C₆    alkyl;

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), —OH and

wherein R²² is C₁-C₆ alkyl substituted with one or more substituentsselected from —(O—CH₂—(CH₂)_(p))_(n)—W and —OR³⁰; and R^(4′) is selectedfrom

wherein R¹⁰⁰ is selected from: hydrogen and C₁₋₁₀ alkyl; and R^(110′) isselected from: —S(O)R⁵¹′ and —S(O)₂R^(51′), preferably S(O)₂R^(51′).

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R¹ is selected from: —OHand

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R¹ is

and R²² is selected from optionally substituted C₁-C₆ alkyl, preferablyan optionally substituted C₂₋₄ alkyl. In some embodiments, R²² is anoptionally substituted C₂₋₃ alkyl.

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R¹ is

and R²² is selected from substituted C₁-C₆ alkyl, preferably asubstituted C₂₋₄ alkyl.

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), the substituents on R²² areindependently selected from —OR³⁰, —(O—CH₂—(CH₂)_(p))_(n)—W, —S(O)R³⁰,—S(O)₂R³⁰, ═O, ═S, ═N(R³⁰), and —CN.

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), the optional substituentson R²² are independently selected from —OR³⁰, —S(O)₂R³⁰, and ═O.

In some embodiments, for the compound or salt of Formula (I), (IZ),(IA), (IB), (IC), (ID), (IE), (IF), or (IG), R³⁰ of —OR³⁰ and —S(O)₂R³⁰,are independently selected from hydrogen and C₁₋₁₀ alkyl, wherein theC₁₋₁₀ alkyl is optionally substituted with one or more substituentsindependently selected from halogen, —OH, —CN, —NO₂, —NH₂, ═O, ═S,—C₁₋₁₀ haloalkyl, —O—C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀carbocycle, and 3- to 10-membered heterocycle.

In some embodiments, for the compound or salt of Formula (I), (IA),(IB), (IC), (ID), (IE), (IF), or (IG), R³⁰ of —OR³⁰ and —S(O)₂R³⁰ isindependently selected at each occurrence from hydrogen and C₁₋₁₀ alkyl.

In some embodiments, for the compound or salt of Formula (I), (IA),(IB), (IC), (ID), (IE), (IF), or (IG), R¹ is selected from

In some embodiments, for the compound or salt of Formula (I), (IA),(IB), (IC), (ID), (IE), (IF), or (IG), R¹ is selected from

In some embodiments, for the compound or salt of Formula (I), (IA),(IB), (IC), (ID), (IE), (IF), or (IG), R^(4′) is

In some cases, R¹⁰⁰ of

selected from: hydrogen and C₁₋₁₀ alkyl.

In some embodiments, for the compound or salt of Formula (I), (IA),(IB), (IC), (ID), (IE), (IF), or (IG), R^(110′) of

is selected from: hydrogen, —S(O)R^(51′), and —S(O)₂R^(51′). In somecases, R^(110′) of

is selected from: —S(O)₂R^(51′).

In some embodiments, for the compound or salt of Formula (I), (IA),(IB), (IC), (ID), (IE), (IF), or (IG), R^(51′) is independently selectedat each occurrence from substituted C₁₋₄ alkyl, optionally substitutedC₃₋₈ carbocyle, optionally substituted 3-10 membered heterocycle,—((CH₂)_(q)—CH₂-D)_(z)-T and optionally substituted C₅₋₃₀ alkyl.

In some embodiments, for the compound or salt of Formula (I), (IA),(IB), (IC), (ID), (IE), (IF), or (IG), R^(51′) is independently selectedat each occurrence from substituted C₁₋₄ alkyl, optionally substitutedC₃₋₈ carbocyle, —((CH₂)_(q)—CH₂-D)_(z)-T and optionally substitutedC₅₋₃₀ alkyl.

In some embodiments, for the compound or salt of Formula (I), (IA),(IB), (IC), (ID), (IE), (IF), or (IG), R^(51′) is independently selectedat each occurrence from substituted C₁₋₄ alkyl, optionally substitutedC₃₋₈ carbocyle, and —((CH₂)_(q)—CH₂-D)_(z)-T.

In some embodiments, for the compound or salt of Formula (I), (IA),(IB), (IC), (ID), (IE), (IF), or (IG), wherein R^(51′) is independentlyselected at each occurrence from substituted C₁₋₄ alkyl, optionallysubstituted C₃₋₈ carbocyle, optionally substituted 3-10 memberedheterocycle, —((CH₂)_(q)—CH₂-D)_(z)-T and optionally substituted C₅₋₃₀alkyl. In some cases z is 3-10. In some cases, z is 3-8. In some cases,z is 4-8. In some cases, z is 5-10.

In some embodiments, for the compound or salt of Formula (I), (IA),(IB), (IC), (ID), (IE), (IF), or (IG), R^(51′) independently selected ateach occurrence from substituted C₁₋₄ alkyl, optionally substituted C₃₋₆carbocycle and optionally substituted 3- to 6-membered heterocycle. Insome cases, R^(51′) independently selected at each occurrence fromsubstituted C₁₋₄ alkyl, C₃₋₆ carbocycle and 3- to 6-memberedheterocycle.

In some embodiments, for the compound or salt of Formula (I), (IA),(IB), (IC), (ID), (IE), (IF), or (IG), R^(51′) is independently selectedat each occurrence from substituted C₁₋₄ alkyl, saturated C₃₋₆carbocycle and saturated 5 to 6-membered heterocycle.

In some embodiments, for the compound or salt of Formula (I), (IA),(IB), (IC), (ID), (IE), (IF), or (IG), R^(51′) is independently selectedat each occurrence from substituted C₁₋₄ alkyl and saturated C₃₋₆carbocycle.

In some embodiments, for the compound or salt of Formula (I), (IA),(IB), (IC), (ID), (IE), (IF), or (IG), the C₁₋₄ alkyl of R^(51′) issubstituted with one or more substituents independently selected from—OR³⁰, C₃₋₁₀ carbocycle and 3- to 10-membered heterocycle.

In some embodiments, for the compound or salt of Formula (I), (IA),(IB), (IC), (ID), (IE), (IF), or (IG), C₁₋₄ alkyl of R^(51′) issubstituted with one or more substituents selected from —OR³⁰, andsaturated C₃₋₆ carbocycle.

In some embodiments, for the compound or salt of Formula (I), (IA),(IB), (IC), (ID), (IE), (IF), or (IG), the C₁₋₄ alkyl of R^(51′) issubstituted with one or more substituents independently selected from—OR³⁰, and —((CH₂)_(q)—CH₂-D)_(z)-T, wherein z is 3 to 20, D is —O—, andT is selected from hydrogen and optionally substituted —C₁-C₆ alkyl.

In some embodiments, for the compound or salt of Formula (I), (IA),(IB), (IC), (ID), (IE), (IF), or (IG), the C₁₋₄ alkyl of R^(51′) issubstituted with one or more substituents independently selected from—((CH₂)_(q)—CH₂-D)_(z)-T, wherein z is 1 to 20, D is —O—, and T isselected from hydrogen and optionally substituted —C₁-C₆ alkyl.

In some embodiments, for the compound or salt of Formula (I), (IA),(IB), (IC), (ID), (IE), (IF), or (IG), the z of —((CH₂)_(q)—CH₂-D)_(z)-Tfor R^(51′) is selected from 1 to 10. In some cases, z is selected from1 to 5. In some cases, z is selected from 3 to 5.

In some embodiments, for the compound or salt of Formula (I), (IA),(IB), (IC), (ID), (IE), (IF), or (IG), R³⁰ of —OR³⁰ for R^(51′) isselected from hydrogen and C₁₋₁₀ alkyl, wherein the C₁₋₁₀ alkyl isoptionally substituted with one or more substituents independentlyselected from halogen, —OH, —CN, —NO₂, —NH₂, ═O, ═S, C₁₋₁₀ alkyl, —C₁₋₁₀haloalkyl, and —O—C₁₋₁₀ alkyl.

In some embodiments, for the compound or salt of Formula (I), (IA),(IB), (IC), (ID), (IE), (IF), or (IG), R³⁰ of —OR³⁰ for R^(51′) isselected from C₁₋₁₀ alkyl wherein the C₁₋₁₀ alkyl is optionallysubstituted with one or more substituents independently selected from—O—C₁₋₁₀ alkyl.

In some embodiments, for the compound or salt of Formula (I), (IA),(IB), (IC), (ID), (IE), (IF), or (IG), R³⁰ of —OR³⁰ for R^(51′) isselected from C₁₋₃ alkyl wherein the C₁₋₁₀ alkyl is optionallysubstituted with one or more substituents independently selected from—O—C₁₋₃ alkyl.

In some embodiments, for the compound or salt of Formula (I), (IA),(IB), (IC), (ID), (IE), (IF), or (IG), R⁴ is selected from

In some embodiments, for the compound or salt of Formula (I), (IA),(IB), (IC), (ID), (IE), (IF), or (IG), R⁴ is selected from

In some embodiments, for the compound or salt of Formula (I), (IA),(IB), (IC), (ID), (IE), (IF), or (IG), R⁴ is selected from

In some cases, R⁴ is selected from

In some embodiments, for the compound or salt of Formula (I), (IA),(IB), (IC), (ID), (IE), (IF), or (IG), R⁴ is selected from

In some embodiments, for the compound or salt of Formula (I), (IA),(IB), (IC), (ID), (IE), (IF), or (IG), R⁴ is selected from

In some embodiments, for the compound or salt of Formula (I), (IA),(IB), (IC), (ID), (IE), (IF), or (IG), R⁴ is selected from

In some embodiments, for the compound or salt of Formula (I), (IA),(IB), (IC), (ID), (IE), (IF), or (IG),

-   R¹ is selected from

-   R²² is selected from optionally substituted C₁-C₆ alkyl;-   wherein the substituents on R²², is independently selected at each    occurrence from: —S(O)R³⁰, and —S(O)₂R³⁰, preferably —S(O)₂R³⁰,    wherein R³⁰ is independently selected at each occurrence from    hydrogen and C₁₋₁₀ alkyl, wherein the C₁₋₁₀ alkyl is optionally    substituted with one or more substituents independently selected    from halogen, —OH, —CN, —NO₂, —NH₂, ═O, ═S, —O—C₁₋₁₀ alkyl, C₂₋₁₀    alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocycle, and 3- to 10-membered    heterocycle.

In some embodiments, for the compound or salt of Formula (I), (IA),(IB), (IC), (ID), (IE), (IF), or (IG),

-   R¹ is selected from —OH and

-   R² is selected from an optionally substituted C₁-C₆ alkoxy    preferably —OCH₃;-   R³ is selected from an optionally substituted C₁-C₆ alkoxy,    preferably —OCH₃; and-   R^(4′) is selected from,

-   R⁵ is selected from hydroxy, and an optionally substituted C₁-C₆    alkoxy, preferably —OH;-   R⁶ and R⁷ are each independently selected from hydrogen, hydroxy,    and C₁-C₆ alkoxy; or R⁶ and R⁷ come together to form

preferably

-   R²² is selected from optionally substituted C₁-C₆ alkyl;-   R¹⁰⁰ is selected from:    -   hydrogen and    -   C₁₋₁₀ alkyl;-   R^(110′) is selected from:    -   hydrogen and —S(O)₂R^(51′), preferably —S(O)₂R^(51′);-   wherein the optional substituents on R²², R^(51′), and T are    independently selected at each occurrence from:    -   halogen, —OR³⁰, —N(R³⁰)₂, —(O—CH₂—(CH₂)_(p))_(n)—W, —NO₂, ═O,        ═S, —S(O)₂R³⁰, and —CN;    -   and    -   C₃₋₁₀ carbocycle and 3-6 membered heterocycle, each of which is        optionally substituted with one or more substituents        independently selected from halogen, —OH, —NO₂, ═O, ═S, —CN,        C₁₋₆ alkyl, —O—C₁₋₆ alkyl;-   R³⁰ is independently selected at each occurrence from hydrogen;    C₁₋₁₀ alkyl, C₃₋₁₀ carbocycle, and 3- to 10-membered heterocycle,    each of which is optionally substituted with one or more    substituents independently selected from halogen, —OH, —CN, —NO₂,    —NH₂, ═O, ═S, C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl, and —O—C₁₋₁₀ alkyl;-   R^(51′) is independently selected at each occurrence from    substituted C₁₋₄ alkyl, optionally substituted C₃₋₈ carbocycle, and    —((CH₂)_(q)—CH₂-D)_(z)-T;-   each D is independently selected from —O—;-   each T is selected from hydrogen and optionally substituted —C₁-C₆    alkyl;-   z is selected from 1 to 10;-   q is selected from 1 to 6;-   each p is selected from 1 or 2;-   each n is selected from 3-7; and-   each W is selected from hydrogen, —OH, —C₁-C₄ alkyl and —O(C₁-C₄    alkyl).

In some embodiments, the compound or salt of Formula (I), (IA), (IB),(IC), (ID), (IE), (IF), or (IG) is selected from:

Compound Group 2

In a second aspect, the present disclosure provides a compoundrepresented by the structure of Formula X:

-   -   or a pharmaceutically acceptable salt thereof, wherein:

-   L is selected from optionally substituted C₁₋₈ alkylene;

-   R¹ is a carboxylic acid or a carboxylic acid isostere;

-   R² is selected from hydrogen and an optionally substituted C₁-C₆    alkoxy group, wherein substituents are independently selected at    each occurrence from hydroxy, halogen, —CN, —NO₂, C₁-C₆ alkoxy, 3-    to 10-membered heterocycle, and C₃₋₁₀ carbocycle, wherein the 3- to    10-membered heterocycle and C₃₋₁₀ carbocycle are each optionally    substituted with one or more substituents independently selected    from hydroxy, halogen, —CN, —NO₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl,    C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, and C₁-C₆ alkoxy C₁-C₆ alkyl;

-   R³ is selected from hydrogen and an optionally substituted C₁-C₆    alkoxy group, wherein the substituents are independently selected at    each occurrence from hydroxy, halogen, —CN, —NO₂, C₁-C₆ alkoxy    group, 3- to 10-membered heterocycle, and C₃₋₁₀ carbocycle, wherein    the 3- to 10-membered heterocycle and C₃₋₁₀ carbocycle, are each    optionally substituted with one or more substituents independently    selected from hydroxy, halogen, —CN, —NO₂, C₁-C₆ alkyl, C₁-C₆    haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, and C₁-C₆ alkoxy C₁-C₆    alkyl; and

-   R⁴ is selected from

-   and optionally substituted 3- to 10-membered heterocycle, and when L    is optionally substituted C₃₋₈ alkylene R⁴ is further selected from    methoxy; and when -L-R¹ is ethyl acetate, tert-butyl acetate, benzyl    acetate, or methyl 2-phenylacetate, R⁴ is not methoxy;    -   wherein the optionally substituted heterocycle of R⁴ may be        substituted with one or more substituents selected from:        hydroxy, halogen, —CN, —NO₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl, ═O,        C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, and C₁-C₆ alkoxy C₁-C₆ alkyl;    -   z is 0, 1, 2, 3, 4 or 5;-   R⁵ is selected from hydrogen, hydroxy, and an optionally substituted    C₁-C₆ alkoxy group, wherein substituents are independently selected    at each occurrence from hydroxy, halogen, —CN, —NO₂, C₁-C₆ alkoxy    group, 3- to 10-membered heterocycle, and C₃₋₁₀ carbocycle, wherein    the 3- to 10-membered heterocycle, and C₃₋₁₀ carbocycle are each    optionally substituted with one or more substituents independently    selected from hydroxy, halogen, —CN, —NO₂, C₁-C₆ alkyl, C₁-C₆    haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, and C₁-C₆ alkoxy C₁-C₆    alkyl;-   R⁶ and R⁷ are each independently selected from hydrogen, hydroxy,    and C₁-C₆ alkoxy; or R⁶ and R⁷ come together to form

-   R²⁵ is independently selected at each occurrence from hydrogen,    optionally substituted C₁-C₆ alkyl, -D-(CH₂—CH₂-G)_(y)-V, optionally    substituted C₃₋₂₀ carbocycle, and optionally substituted 3- to    20-membered heterocycle,    -   wherein when R²⁵ is optionally substituted C₁-C₆ alkyl, the        substituents on C₁-C₆ alkyl are independently selected at each        occurrence from halogen, —OH, —CN, —NO₂, —NH₂, ═O, ═S,        —C(O)N(R³¹)₂, —OC(O)N(R³¹)₂, —C(O)OR³¹, —P(O)(R³¹)₂, —C₁₋₁₀        haloalkyl, —O—C₁₋₁₀ alkyl, —O—C₁₋₁₀ alkyl-CN, —O—C₁₋₁₀        alkyl-C(O)OR³¹, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₂₀ carbocycle,        and 3- to 20-membered heterocycle;    -   wherein when R²⁵ is optionally substituted C₃₋₂₀ carbocycle or        optionally substituted 3- to 20-membered heterocycle, the        substituents on C₃₋₂₀ carbocycle and 3- to 20-membered        heterocycle are independently selected at each occurrence from        halogen, —OR³¹, —SR³¹, —N(R³¹)₂, —C(O)R³¹, —C(O)N(R³¹)₂,        —N(R³¹)C(O)R³¹, —C(O)OR³¹, —OC(O)R³¹, —S(O)R³¹, —S(O)₂R³¹,        —P(O)(OR³¹)₂, —OP(O)(OR³¹)₂, —NO₂, ═O, ═S, ═N(R³¹), —CN, C₁₋₆        alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;    -   wherein D is selected from a bond or —O—;    -   each G is independently selected from —O—, —NR³²—, —S—, or        —SO₂—;    -   each y is selected from 1-20;    -   each V is selected from hydrogen and optionally substituted        —C₁-C₆ alkyl;-   R³⁰ is independently selected at each occurrence from hydrogen;    C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocycle, and 3-    to 10-membered heterocycle, each of which is optionally substituted    with one or more substituents independently selected from halogen,    —OH, —OSi(C₁-C₆alkyl)₃, —CN, —NO₂, —NH₂, ═O, ═S, C₁₋₁₀ alkyl, —C₁₋₁₀    haloalkyl, —O—C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀    carbocycle, and 3- to 10-membered heterocycle;-   R′ and R″ are independently selected at each occurrence from    hydrogen, halogen, —OR³¹, and C₁₋₈ alkyl optionally substituted with    one or more substituents independently selected from halogen and    —OR³¹; and-   R³¹ is independently selected at each occurrence from: hydrogen; and    C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₂ carbocycle, and 3-    to 12-membered heterocycle, each of which is optionally substituted    with one or more substituents independently selected from halogen,    —OH, —OSi(C₁-C₆alkyl)₃, —CN, —NO₂, —NH₂, ═O, ═S, C₁₋₁₀ alkyl, —C₁₋₁₀    haloalkyl, —O—C₁₋₁₀ alkyl, —O—C₁₋₁₀ alkyl-OH, C₂₋₁₀ alkenyl, C₂₋₁₀    alkynyl, C₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle;-   R³² is independently selected at each occurrence from: hydrogen; and    C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocycle, and 3-    to 10-membered heterocycle, each of which is optionally substituted    with one or more substituents independently selected from halogen,    —OH, —CN, —NO₂, —NH₂, ═O, ═S, C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl,    —O—C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocycle, and    3- to 10-membered heterocycle; and-   wherein the substituents on V and L are independently selected at    each occurrence from:    -   halogen, —OR³⁰, —N(R³⁰)₂, —SR³⁰, —C(O)R³⁰, —C(O)N(R³⁰)₂,        —N(R³⁰)C(O)R³⁰, —C(O)OR³⁰, —OC(O)R³⁰, —S(O)R³⁰, —S(O)₂R³⁰,        —P(O)(OR³⁰)₂, —OP(O)(OR³⁰)₂, —NO₂, ═O, ═S, ═N(R³⁰), and —CN;    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, each of which is        optionally substituted with one or more substituents        independently selected from halogen, —OR³⁰, —SR³⁰, —N(R³⁰)₂,        —C(O)R³⁰, —C(O)N(R³⁰)₂, —N(R³⁰)C(O)R³⁰, —C(O)OR³⁰, —OC(O)R³⁰,        —S(O)R³⁰, —S(O)₂R³⁰, —P(O)(OR³⁰)₂, —OP(O)(OR³⁰)₂, —NO₂, ═O, ═S,        ═N(R³⁰), —CN, C₃₋₁₀ carbocycle and 3- to 10-membered        heterocycle; and    -   C₃₋₁₀ carbocycle and 3- to 10-membered heterocycle each of which        is optionally substituted with one or more substituents        independently selected from halogen, —OR³⁰, —SR³⁰, —N(R³⁰)₂,        —C(O)R³⁰, —C(O)N(R³⁰)₂, —N(R³⁰)C(O)R³⁰, —C(O)OR³⁰, —OC(O)R³⁰,        —S(O)R³⁰, —S(O)₂R³⁰, —P(O)(OR³⁰)₂, —OP(O)(OR³⁰)₂, —NO₂, ═O, ═S,        ═N(R³⁰), —CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, and C₂₋₆        alkynyl.

In certain embodiments, the compound of Formula (X) is represented byFormula (XA):

or a salt thereof.

In certain embodiments, the compound of Formula (X) is represented byFormula (XB):

or a salt thereof.

In certain embodiments, the compound of Formula (X) is represented byFormula (XC):

or a salt thereof.

In certain embodiments, the compound of Formula (X) is represented byFormula (XD):

or a salt thereof.

In certain embodiments, the compound of Formula (X) is represented byFormula (XE):

or a salt thereof.

In certain embodiments, the compound of Formula (X) is represented byFormula (XF):

or a salt thereof.

In certain embodiments, the compound of Formula (X) is represented byFormula (XG):

or a salt thereof.

In certain embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R¹ is a carboxylic acid isotere.The carboxylic acid functional group can be an important constituent ofa pharmacophore, however, the presence of this moiety can also beresponsible for significant drawbacks, including metabolic instability,toxicity, as well as limited passive diffusion across biologicalmembranes. To avoid potential shortcomings while retaining the desiredattributes of the carboxylic acid moiety, R¹ may be selected from acarboxylic acid isostere. A carboxylic acid isostere is a chemicalmoiety that demonstrates similar or improved physical properties andbiological properties relative to a carboxylic acid group.

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), the carboxylic acid isostere ofR¹ is selected from: ester, hydroxamic acid, hydroxamic ester,phosphonic acid, phosphinic acid, sulfonic acid, sulfinic acid, sulfone,sulfonamide, acylsulfonamide, sulfonylurea, acylurea, tetrazole,thiazolidinedione, oxazolidinedione, oxadiazol-5(4H)-one,thiadiazol-5(4H)-thione, oxathiadiazole-2-oxide, oxadiazol-5(4H)-thione,isoxazole, tetramic acid, cyclopentane 1,3-dione, cyclopentane1,2-dione, squaric acid, and substituted phenol.

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), the carboxylic acid isostere ofR¹ is selected from: hydroxamic acid, hydroxamic ester, phosphonic acid,phosphinic acid, sulfonic acid, sulfinic acid, a sulfone, sulfonamide,acylsulfonamide, sulfonylurea, acylurea, tetrazole, thiazolidinedione,oxazolidinedione, oxadiazol-5(4H)-one, thiadiazol-5(4H)-thione,oxathiadiazole-2-oxide, oxadiazol-5(4H)-thione, isoxazole, tetramicacid, cyclopentane 1,3-dione, cyclopentane 1,2-dione, squaric acid, andsubstituted phenol.

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R¹ of -L-R¹ is selected from:ester, carboxylic acid, hydroxamic acid, hydroxamic ester, phosphonicacid, phosphinic acid, sulfonic acid, sulfinic acid, a sulfone,sulfonamide, acylsulfonamide, sulfonylurea, acylurea, tetrazole,thiazolidinedione, oxazolidinedione, oxadiazol-5(4H)-one ,thiadiazol-5(4H)-thione, oxathiadiazole-2-oxide, oxadiazol-5(4H)-thione,isoxazole, tetramic acid, cyclopentane 1,3-dione, cyclopentane1,2-dione, squaric acid, and substituted phenol.

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R¹ of -L-R¹ is selected from:carboxylic acid, hydroxamic acid, hydroxamic ester, phosphonic acid,phosphinic acid, sulfonic acid, sulfinic acid, sulfonamide, a sulfone,acylsulfonamide, sulfonylurea, acylurea, tetrazole, thiazolidinedione,oxazolidinedione, oxadiazol-5(4H)-one , thiadiazol-5(4H)-thione,oxathiadiazole-2-oxide, oxadiazol-5(4H)-thione, isoxazole, tetramicacid, cyclopentane 1,3-dione, cyclopentane 1,2-dione, squaric acid, andsubstituted phenol.

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), when R¹ of -L-R¹ is selectedfrom: carboxylic acid, hydroxamic acid, hydroxamic ester, phosphonicacid, phosphinic acid, sulfonic acid, sulfinic acid, sulfonamide,sulfone, acylsulfonamide, sulfonylurea, acylurea, tetrazole,thiazolidinedione, oxazolidinedione, oxadiazol-5(4H)-one ,thiadiazol-5(4H)-thione, oxathiadiazole-2-oxide, oxadiazol-5(4H)-thione,isoxazole, tetramic acid, cyclopentane 1,3-dione, cyclopentane1,2-dione, squaric acid, and substituted phenol, R⁴ is not methoxy.

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), when R¹ of -L-R¹ is selectedfrom: ester, carboxylic acid, hydroxamic acid, hydroxamic ester,phosphonic acid, phosphinic acid, sulfonic acid, sulfinic acid,sulfonamide, sulfone, acylsulfonamide, sulfonylurea, acylurea,tetrazole, thiazolidinedione, oxazolidinedione, oxadiazol-5(4H)-one,thiadiazol-5(4H)-thione, oxathiadiazole-2-oxide, oxadiazol-5(4H)-thione,isoxazole, tetramic acid, cyclopentane 1,3-dione, cyclopentane1,2-dione, squaric acid, and substituted phenol, R⁴ is not methoxy.

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R¹ of -L-R¹ is carboxylic acid.In some embodiments, -L-R¹ is represented by

In some embodiments, when -L-R¹ is represented by

R⁴ is not methoxy. In some embodiments, when -L-R¹ is represented by

L is unsubstituted. In some embodiments, when -L-R¹ is represented by

and L is selected from C₃₋₈ alkylene, L is unsubstituted. In someembodiments, when -L-R¹ is represented by

and L is selected from C₁₋₂ alkylene, L is substituted.

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R¹ of -L-R¹ is an ester. In someembodiments, -L-R¹ is represented by

In some embodiments, R⁴¹ is selected from a C₁₋₆ alkyl and benzyl. Insome embodiments, R⁴¹ is a C₁₋₆ alkyl. In some embodiments, R⁴¹ is aC₁₋₄ alkyl. In some embodiments, R⁴¹ is a methyl. In some embodiments,R⁴¹ is a ethyl. In some embodiments, R⁴¹ is selected from isopropyl andt-butyl. In some embodiments, R⁴¹ is isopropyl. In some embodiments, R⁴¹is n-propyl. In some embodiments, R⁴¹ is t-butyl. In some embodiments,R⁴¹ is n-butyl. In some embodiments, R⁴¹ is benzyl. In some embodiments,-L-R¹ is

In some embodiments, -L-R¹ is

In some embodiments, -L-R¹ is

In some embodiments, when -L-R¹ is represented by

L is selected from C₂₋₈ alkylene. In some embodiments, when -L-R¹ isrepresented by

and L is C₁ alkylene, R⁴ is not methoxy. In some embodiments, -L-R¹ isrepresented by

R⁴ is not methoxy. In some embodiments, when -L-R¹ is ethyl acetate,tert-butyl acetate, benzyl acetate or methyl 2-phenylacetate, R⁴ is notmethoxy. In some embodiments, when -L-R¹ is selected from

R⁴ is not methoxy. In some embodiments, when -L-R¹ is

R⁴ is not methoxy. In some embodiments, when -L-R¹ is

R⁴ is not methoxy. In some embodiments, when -L-R¹ is

R⁴ is not methoxy. In some embodiments, when -L-R¹ is

R⁴ is not methoxy.

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R¹ of -L-R¹ is hydroxamic ester.In some embodiments, -L-R¹ is represented by

In some embodiments, -L-R¹ is represented by

In some embodiments, -L-R¹ is represented

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R¹ of -L-R¹ is selected from:hydroxamic acid, phosphonic acid, phosphinic acid, sulfonic acid,sulfinic acid, sulfonamide, sulfone, acylsulfonamide, sulfonylurea,acylurea, tetrazole, thiazolidinedione, oxazolidinedione,oxadiazol-5(4H)-one, thiadiazol-5(4H)-thione, oxathiadiazole-2-oxide,oxadiazol-5(4H)-thione, isoxazole, tetramic acid, cyclopentane1,3-dione, cyclopentane 1,2-dione, squaric acid, and substituted phenol.

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R¹ of -L-R¹ is hydroxamic acid.In some embodiments, -L-R¹ is represented by

In some embodiments, -L-R¹ is represented by

In some embodiments, -L-R¹ is represented by

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R¹ of -L-R¹ is phosphoric acid.In some embodiments, -L-R¹ is represented by

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R¹ of -L-R¹ is phosphonic acid.In some embodiments, -L-R¹ is represented by

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R¹ of -L-R¹ is sulfonic acid. Insome embodiments, -L-R¹ is represented by

In some embodiments, the carboxylic acid isostere of R¹ may be a salt,for example -L-R¹ is represented by

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R¹ of -L-R¹ is sulfinic acid. Insome embodiments, -L-R¹ is represented by

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R¹ of -L-R¹ is sulfonamide. Insome embodiments, -L-R¹ is represented by

In some embodiments, -L-R¹ is represented by

In some embodiments, -L-R¹ is represented by

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R¹ of -L-R¹ is sulfone. In someembodiments, -L-R¹ is represented by

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R¹ of -L-R¹ is acylsulfonamide.In some embodiments, -L-R¹ is represented by

In some embodiments, -L-R¹ is represented by

In some embodiments, -L-R¹ is represented by

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R¹ of -L-R¹ is sulfonyl urea. Insome embodiments, -L-R¹ is represented by

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R¹ of -L-R¹ is acylurea. In someembodiments, -L-R¹ is represented by

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R¹ of -L-R¹ is tetrazole. In someembodiments, -L-R¹ is represented by

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R¹ of -L-R¹ is thiazolidinedione.In some embodiments, -L-R¹ is represented by

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R¹ of -L-R¹ is oxazolidinedione.In some embodiments, -L-R¹ is represented by

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R¹ of -L-R¹ isoxadiazol-5(4H)-one. In some embodiments, -L-R¹ is represented by

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R¹ of -L-R¹ isthiadiazol-5(4H)-thione. In some embodiments, -L-R¹ is represented by

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R¹ of -L-R¹ isoxathiadiazole-2-oxide. In some embodiments, -L-R¹ is represented by

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R¹ of -L-R¹ isoxadiazol-5(4H)-thione. In some embodiments, -L-R¹ is represented by

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R¹ of -L-R¹ is isoxazole. In someembodiments, -L-R¹ is represented by

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R¹ of -L-R¹ is tetramic acid. Insome embodiments, -L-R¹ is represented by

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R¹ of -L-R¹ is cyclopentane1,3-dione. In some embodiments, -L-R¹ is represented by

In some embodiments, -L-R¹ is represented by

In some embodiments, -L-R¹ is represented by

In some embodiments, -L-R¹ is represented by

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R¹ of -L-R¹ is cyclopentane1,2-dione. In some embodiments, -L-R¹ is represented by

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R¹ of -L-R¹ is squaric acid. Insome embodiments, -L-R¹ is represented by

In some embodiments, -L-R¹ is represented by

In some embodiments, -L-R¹ is represented by

In some embodiments, -L-R¹ is represented by

In some embodiments, -L-R¹ is represented by

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R¹ of -L-R¹ is substitutedphenol. In some embodiments, the substituted phenol of -L-R¹ isoptionally substituted with one or more substituents independentlyselected from: halogen, —S—, —S(O)—, and —S(O)₂—. In some embodiments,-L-R¹ is represented by

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), the substituted phenol of -L-R¹is substituted with one or more substituents selected from halogen. Insome embodiments, -L-R¹ is represented by

In some embodiments, -L-R¹ is represented by

In some embodiments, -L-R¹ is represented by

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), -L-R¹ is represented by

In some embodiments, -L-R¹ is represented by

In some embodiments, -L-R¹ is represented by

In some embodiments, -L-R¹ is represented by

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), -L-R¹ is represented by

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), -L-R¹ is represented by

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), -L-R¹ is represented by

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), L is an optionally substitutedC₁₋₈ alkylene. In some embodiments, the optionally substituted C₁₋₈alkylene is selected from methylene, ethylene, propylene, butylene,pentylene, hexylene, heptylene, and octylene. In some embodiments, forthe compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF),or (XG), when L is an optionally substituted C₁₋₂ alkylene, R⁴ is notmethoxy. In some embodiments, for the compound or salt of Formula (X),(XA), (XB), (XC), (XD), (XE), (XF), or (XG), L is optionally substitutedby one or more substituents independently selected from halogen, —OR³⁰,—N(R³⁰)₂, —SR³⁰, —C(O)R30, —C(O)N(R³⁰)₂, —N(R³⁰)C(O)R³⁰, —C(O)OR³⁰,—OC(O)R³⁰, —S(O)R³⁰, —S(O)₂R³⁰, —NO₂, ═O, C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl,and —CN. In some embodiments, for the compound or salt of Formula (X),(XA), (XB), (XC), (XD), (XE), (XF), or (XG), L is optionally substitutedby one or more substituents independently selected from halogen, —OR³⁰,—N(R³⁰)₂, —SR³⁰, —C(O)R30, —C(O)N(R³⁰)₂, —(O—CH₂—(CH₂)_(p))_(n)—W,—N(R³⁰)C(O)R³⁰, —C(O)OR³⁰, —OC(O)R³⁰, —S(O)R³⁰, —S(O)₂R³⁰, —NO₂, C₁₋₁₀alkyl, C₁₋₁₀ haloalkyl, and —CN. In some embodiments, for the compoundor salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), Lis optionally substituted by one or more substituents independentlyselected from halogen, —OR³⁰, —N(R³⁰)₂, —SR³⁰, —C(O)R³⁰, —C(O)N(R³⁰)₂,—N(R³⁰)C(O)R³⁰, —C(O)OR³⁰, —OC(O)R³⁰, —S(O)R³⁰, —S(O)₂R³⁰, —NO₂, C₁₋₁₀alkyl, C₁₋₁₀ haloalkyl, and —CN. In some embodiments, for the compoundor salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), Lis unsubstituted, e.g., L is methylene, ethylene or propylene.

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), L is an optionally substitutedC₁₋₈ alkylene wherein L is optionally substituted by one or moresubstituents independently selected from —(O—CH₂—(CH₂)_(p))_(n)—W,wherei each p is selected from 1 or 2; each n is selected from 3-7; andeach W is selected from hydrogen, —OH, —C₁-C₄ alkyl and —O(C₁-C₄ alkyl).

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), when L is an optionallysubstituted C₃₋₈ alkylene, R⁴ is further selected from methoxy.

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), L is an optionally substitutedC₃₋₈ alkylene selected from propylene, butylene, pentylene, hexylene,heptylene, and octylene any one of which is optionally substituted byone or more substituents independently selected from halogen, —OR³⁰,—N(R³⁰)₂, —SR³⁰, —C(O)R³⁰, —C(O)N(R³⁰)₂, —N(R³⁰)C(O)R³⁰, —C(O)OR³⁰,—OC(O)R³⁰, —S(O)R³⁰, —S(O)₂R³⁰, —NO₂, ═O, C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl,and —CN. In some embodiments, for the compound or salt of Formula (X),(XA), (XB), (XC), (XD), (XE), (XF), or (XG), L is optionally substitutedby one or more substituents independently selected from halogen, —OR³⁰,—N(R³⁰)₂, —SR³⁰, —C(O)R³⁰, —C(O)N(R³⁰)₂, —N(R³⁰)C(O)R³⁰, —C(O)OR³⁰,—OC(O)R³⁰, —S(O)R³⁰, —S(O)₂R³⁰, —NO₂, C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, and—CN.

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), L is a substituted C₁₋₈ alkylene.In some embodiments, the substituted C₁₋₈ alkylene is selected frommethylene, ethylene, propylene, butylene, pentylene, hexylene,heptylene, and octylene.

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), when L is a substituted C₃₋₈alkylene, R⁴ is further selected from methoxy.

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), L is a C₃₋₈ alkylene substitutedwith one or more substituents independently selected from halogen,—OR³⁰, —N(R³⁰)₂, —SR³⁰, —C(O)R³⁰, —C(O)N(R³⁰)₂, —N(R³⁰)C(O)R³⁰,—C(O)OR³⁰, —OC(O)R³⁰, —S(O)R³⁰, —S(O)₂R³⁰, —NO₂, C₁₋₁₀ alkyl, C₁₋₁₀haloalkyl, and —CN.

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), L is a C₃₋₈ alkylene substitutedwith one or more substituents independently selected from halogen,—OR³⁰, —N(R³⁰)₂, —SR³⁰, —C(O)R³⁰, —C(O)N(R³⁰)₂, —N(R³⁰)C(O)R³⁰,—C(O)OR³⁰, —OC(O)R³⁰, —S(O)R³⁰, —S(O)₂R³⁰, —NO₂, ═O, C₁₋₁₀ alkyl, C₁₋₁₀haloalkyl, and —CN.

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R² is selected from hydrogen andan optionally substituted C₁-C₆ alkoxy group, wherein substituents areindependently selected at each occurrence from hydroxy, halogen, —CN,—NO₂, and C₁-C₆ alkoxy. In some embodiments, R² is selected fromhydrogen and an optionally substituted C₁-C₆ alkoxy, whereinsubstituents are independently selected at each occurrence from hydroxy,halogen, —NO₂, and C₁-C₆ alkoxy.

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R² is selected from hydrogen andC₁-C₆ alkoxy. In some embodiments, R² is selected from hydrogen and—OMe. In some embodiments, R² is —OMe.

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R³ is selected from hydrogen andan optionally substituted C₁-C₆ alkoxy, wherein the substituents areindependently selected at each occurrence from hydroxy and C₁-C₆ alkoxy.In some embodiments, R³ is selected from hydrogen and C₁-C₆ alkoxy.

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R³ is selected from C₁-C₆ alkoxy.In some embodiments, R³ is —OMe.

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R⁵ is selected from hydrogen,hydroxy, and an optionally substituted C₁-C₆ alkoxy group, whereinsubstituents are independently selected at each occurrence from hydroxy,halogen, —CN, —NO₂, and C₁-C₆ alkoxy.

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R⁵ is hydroxy.

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R⁶ and R⁷ are each independentlyselected from hydrogen, hydroxy, and C₁-C₆ alkoxy. In some cases, R⁶ andR⁷ are each independently selected from hydrogen and hydroxy. In someembodiments, R⁶ and R⁷ are each hydrogen. In some embodiments, R⁶ ishydrogen and R⁷ is C₁-C₆ alkoxy . In some embodiments, R⁶ is hydrogenand R⁷ is. In some embodiments, R⁶ and R⁷ come together to form

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R⁴ is selected from

and optionally substituted 3- to 10-membered heterocycle.

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R⁴ is

In some embodiments, z is 0, 1, 2, 3, 4 or 5. In some embodiments, z is1, 2, 3, 4 or 5. In some embodiments, z is 1, 2 or 3. In someembodiments, z is 2, 3 or 4. In some embodiments, when z is 0, R²⁵ isselected from: optionally substituted C₁-C₆ alkyl, optionallysubstituted 3- to 10-membered heterocycle, and optionally substitutedC₃₋₁₀ carbocycle. In some embodiments, when z is 1, R²⁵ is selectedfrom: optionally substituted C₁-C₆ alkyl, optionally substituted 3- to10-membered heterocycle, and optionally substituted C₃₋₁₀ carbocycle.

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), each R′ and R″ of

is independently selected from hydrogen, —OR³¹, and C₁₋₃ alkyloptionally substituted with one or more —OR³¹. In some embodiments, R′and R″ are the same substitutent, for example R′ is methyl and R″ ismethyl or R′ is hydrogen and R″ is hydrogen. In some embodiments, eachR′ and R″ are independently selected from a different substituent, forexample R′ is methyl and R″ is ethyl. In some embodiments, each R′ andR″ are independently selected from hydrogen and C₁₋₃ alkyl optionallysubstituted with one or more —OR³¹. In some embodiments, R′ and R″ areeach C₁₋₃ alkyl optionally substituted with one or more —OR³¹. In someembodiments, R′ and R″ are each hydrogen.

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R²⁵ of

is selected from hydrogen, optionally substituted C₁-C₆ alkyl,-D-(CH₂—CH₂-G)_(y)-V, optionally substituted 3- to 10-memberedheterocycle, and optionally substituted C₃₋₁₀ carbocycle.

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R²⁵ of

is hydrogen. In some embodiments, R⁴ is

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R²⁵ of

is an optionally substituted C₁-C₆ alkyl. In some embodiments, theoptionally substituted C₁-C₆ alkyl of R²⁵ is substituted with one ormore substituents selected from —OH and —O—C₁₋₆ alkyl. In someembodiments, R⁴ is selected from:

some embodiments, R⁴ is

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R²⁵ of

is a substituted C₁-C₆ alkyl with substituents selected from—P(O)(R³¹)₂. In some embodiments, R³¹ of —P(O)(R³¹)₂ is a C₁₋₆ alkylsubstituted with one or more substituents selected —OH and —O—C₁₋₆alkyl. In some embodiments, R⁴ is represented by

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R²⁵ of

is -D-(CH₂—CH₂-G)_(y)-V. In some embodiments, D is a bond. In someembodiments, D is —O—. In some embodiments, y of -D-(CH₂—CH₂-G)_(y)-V is1 to 1000. In some embodiments, y is 1 to 800. In some embodiments, y is1 to 500. In some embodiments, y is 1 to 300. In some embodiments, y is1 to 100. In some embodiments, y is 1 to 50. In some embodiments, y is 1to 25, such as 1 to 10 or 1 to 8. In some embodiments, y is 3 to 1000.In some embodiments, y is 10 to 1000. In some embodiments, y is 50 to1000. In some embodiments, y is 100 to 1000. In some embodiments, y is200 to 1000. In some embodiments, y is 500 to 1000. In some embodiments,y of -D-(CH₂—CH₂-G)_(y)-V for R²⁵ is 3 to 10. In some embodiments, y of-D-(CH₂—CH₂-G)_(y)-V for R²⁵ is 5 to 10. In some embodiments, y is 0, 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25,or 100. In some embodiments, y is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 25, or 100.

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R²⁵ of

is represented by -D-(CH₂—CH₂-G)_(y)-V and G of -D-(CH₂—CH₂-G)_(y)-V ateach occurrence is —O—. In some embodiments, R⁴ is selected from

In some embodiments, R⁴ is selected from

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R²⁵ of

is represented by -D-(CH₂—CH₂-G)_(y)-V. In some embodiments, D isselected from a bond or —O—. In some embodiments, D is a bond. In someembodiments, D is —O—. In some embodiments, when z is 0, D is a bond. Insome embodiments, when z is 1, D is a bond. In some embodiments, when zis 2, D is a bond. In some embodiments, when D is —O—, z is selectedfrom 1, 2, 3, 4, or 5. In some embodiments, when D is —O—, z is selectedfrom 2, 3, 4, or 5.

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R²⁵ of

is represented by -D-(CH₂—CH₂)_(y)-V and G of -D-(CH₂—CH₂-G)_(y)-V ateach occurrence is —NR³²—. In some embodiments, each R³² of —NR³²— isindependently selected from hydrogen; and C₁₋₁₀ alkyl, each of which isoptionally substituted with one or more substituents independentlyselected from halogen, —OH, C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl, and —O—C₁₋₁₀alkyl.

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R²⁵ of

is represented by -D-(CH₂—CH₂-G)_(y)-V, and V is an optionallysubstituted C₁-C₆ alkyl. In some embodiments, the C₁-C₆ alkyl of V isoptionally substituted with one or more substituents independentlyselected from —(O—CH₂—(CH₂)_(p))_(n)—W wherein

-   each p is selected from 1 or 2; each n is selected from 3 to 7; each    W is selected from hydrogen, —OH, —C₁-C₄ alkyl, and —O(C₁-C₄ alkyl).

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R²⁵ of

is represented by -D-(CH₂—CH₂-G)_(y)-V, and V is an optionallysubstituted C₁-C₆ alkyl. In some embodiments, the C₁-C₆ alkyl of V isoptionally substituted with one or more substituents independentlyselected from halogen, —OR³⁰, —N(R³⁰)₂, —SR³⁰, —C(O)R³⁰, —C(O)N(R³⁰)₂,—N(R³⁰)C(O)R³⁰, —C(O)OR³⁰, —OC(O)R³⁰, —S(O)R³⁰, —S(O)₂R³⁰, —P(O)(OR³⁰)₂,—OP(O)(OR³⁰)₂, —NO₂, ═O, ═S, ═N(R³⁰), and —CN.

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R²⁵ of

is represented by -D-(CH₂—CH₂-G)_(y)-V, and V is an optionallysubstituted C₁-C₆ alkyl. In some embodiments, the C₁-C₆ alkyl of V isoptionally substituted with one or more substituents independentlyselected from halogen, —OR³⁰, —N(R³⁰)₂, —(O—CH₂—(CH₂)_(p))_(n)—W, —SR³⁰,—C(O)R³⁰, —C(O)N(R³⁰)₂, —N(R³⁰)C(O)R³⁰, —C(O)OR³⁰, —OC(O)R³⁰, —S(O)R³⁰,—S(O)₂R³⁰, —P(O)(OR³⁰)₂, —OP(O)(OR³⁰)₂, —NO₂, ═O, ═S, ═N(R³⁰), and —CN.

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R²⁵ of

is represented by -D-(CH₂—CH₂-G)_(y)-V, and V is a substituted C₁-C₆alkyl with one or more substituents independently selected from —OR³⁰and —N(R³⁰)₂. In some embodiments, V is a substituted C₁-C₆ alkyl withone or more substituents independently selected from —OR³⁰ wherein R³⁰is selected from hydrogen; and C₁₋₅ alkyl, C₃₋₆ carbocycle, and 3- to6-membered heterocycle, each of which is optionally substituted with oneor more substituents independently selected from halogen, —OH, —CN,—NO₂, —NH₂, ═O, ═S, C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl, and —O—C₁₋₁₀ alkyl.

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R²⁵ of

is an optionally substituted 3- to 6-membered heterocycle. In someembodiments, the 3- to 6-membered heterocycle is saturated. In someembodiments, the 3- to 6-membered heterocycle is unsaturated. In someembodiments, the optionally substituted 3- to 6-membered heterocyclecomprises at least one heteroatom selected from nitrogen, oygen, sulfur,and any combination thereof. In some embodiments, the optionallysubstituted 3- to 6-membered heterocycle comprises at least oneheteroatom selected from N and O wherein the 3- to 6-memberedheterocycle is optionally substituted with C₁₋₆ alkyl. In someembodiments, R⁴ is selected from

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R²⁵ of

is an optionally substituted C₃₋₁₀ carbocycle. In some embodiments, R²⁵is an optionally substituted C₃₋₆ carbocycle. In some embodiments, theC₃₋₆ carbocycle is saturated. In some embodiments, C₃₋₆ carbocycle isunsaturated. In some embodiments, R⁴ is selected from:

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R⁴ is

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R⁴ is selected from:

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R⁴ is selected from:

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R⁴ is selected from:

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R⁴ is selected from:

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is selected from:

In some embodiments, R⁴ is

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), when R¹ is hydroxy, R⁴ is not

In some embodiments, R⁴ is not

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R⁴ is selected from:

In some embodiments, R⁴ is selected from

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R⁴ is selected from:

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R⁴ is selected from:

In some embodiments, R⁴ is from

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), L is selected from optionallysubstituted C₁₋₆ alkylene;

-   R¹ is a sulfone;-   R² is selected from hydrogen and an optionally substituted C₁-C₆    alkoxy;-   R³ is selected from hydrogen and an optionally substituted C₁-C₆    alkoxy; and-   R⁴ is selected from

-   and optionally substituted 3- to 10-membered heterocycle, preferably

-   -   wherein the optionally substituted heterocycle of R⁴ may be        substituted with one or more substituents selected from:        hydroxy, halogen, —CN, —NO₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl, ═O,        C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, and C₁-C₆ alkoxy C₁-C₆ alkyl;    -   z is 0, 1, 2, 3, 4 or 5;

-   R⁵ is selected from hydrogen, hydroxy, and an optionally substituted    C₁-C₆ alkoxy group;

-   R⁶ and R⁷ are each independently selected from hydrogen, hydroxy,    and C₁-C₆ alkoxy; or R⁶ and R⁷ come together to form

-   preferably R⁶ and R⁷ come together to form

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), L is selected from optionallysubstituted C₁₋₅ alkylene.

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R¹ is selected from a carboxylicacid, an ester, a sulfone, and a sulfonic acid.

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), the ester is represented by—C(O₂)(C₁₋₆ alkyl), wherein the C₁₋₆ alkyl is optionally substituted byone or more substituents selected from halogen, —OH, —NO₂, ═O, —O—C₁₋₆alkyl andthe sulfone is represented by —S(O)₂C₁₋₆ alkyl ,wherein theC₁₋₆ alkyl is optionally substituted by one or more substituentsselected from halogen, —OH, —NO₂, ═O, —O—C₁₋₆ alkyl.

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG),R¹ is selected from

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R¹ is selected from a sulfone anda sulfonic acid. In some embodiments, R¹ is selected from

In some cases, R¹ is selected from

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R¹ is selected from

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R¹ is selected from a sulfone anda ester. In some cases, R¹ is selected from

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R⁴ is

wherein R′ and R″ are independently selected at each occurrence fromhydrogen, hydroxy, and —OR³¹, wherein R³¹ is C₁₋₁₀ alkyl. In some cases,z is selected from 1, 2, and 3.

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R²⁵ is selected from hydrogen,and -D-(CH₂—CH₂-G)_(y)-V, wherein D is —O—, G is —O—, y is 1-3, and V isselected from —C₁-C₆ alkyl and hydrogen.

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R⁴ is methoxy.

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R⁴ is selected from

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R⁴ is selected from

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R⁴ is selected from

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R⁴ is selected from

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R⁴ is selected from

In some cases, R⁴ is selected from

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG),

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG),

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R⁴ is selected from:

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R⁴ is selected from

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R⁴ is selected from:

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R⁴ is selected from:

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R⁴ is selected from:

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R⁴ is selected from:

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R⁴ is selected from:

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R⁴ is selected from:

In some embodiments, for the compound or salt of Formula (X), (XA),(XB), (XC), (XD), (XE), (XF), or (XG), R⁴ is selected from:

In some embodiments, the compound or salt of Formula (I) is selectedfrom:

Compound Group 3

In a third aspect, the present disclosure provides a compoundrepresented by the structure of Formula (L):

-   -   or a pharmaceutically acceptable salt thereof, wherein:

R¹ is selected from

3- to 10-membered heterocycle, and C₃₋₁₀ carbocycle, wherein the 3- to10-membered heterocycle and C₃₋₁₀ carbocycle are each optionallysubstituted with one or more substituents independently selected fromR³³;

R² is selected from hydrogen and an optionally substituted C₁-C₆ alkoxygroup, wherein substituents are independently selected at eachoccurrence from hydroxy, halogen, —CN, —NO₂, C₁-C₆ alkoxy, 3- to10-membered heterocycle, and C₃₋₁₀ carbocycle, wherein the 3- to10-membered heterocycle and C₃₋₁₀ carbocycle are each optionallysubstituted with one or more substituents independently selected fromhydroxy, halogen, —CN, —NO₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆ alkoxy, and C₁-C₆ alkoxy C₁-C₆ alkyl;

R³ is selected from hydrogen and an optionally substituted C₁-C₆ alkoxygroup, wherein the substituents are independently selected at eachoccurrence from hydroxy, halogen, —CN, —NO₂, C₁-C₆ alkoxy group, 3- to10-membered heterocycle, and C₃₋₁₀ carbocycle, wherein the 3- to10-membered heterocycle and C₃₋₁₀ carbocycle, are each optionallysubstituted with one or more substituents independently selected fromhydroxy, halogen, —CN, —NO₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆ alkoxy, and C₁-C₆ alkoxy C₁-C₆ alkyl; and

R⁴ is

R⁵ is selected from hydrogen, hydroxy, and an optionally substitutedC₁-C₆ alkoxy group, wherein substituents are independently selected ateach occurrence from hydroxy, halogen, —CN, —NO₂, C₁-C₆ alkoxy group, 3-to 10-membered heterocycle, and C₃₋₁₀ carbocycle, wherein the 3- to10-membered heterocycle, and C₃₋₁₀ carbocycle are each optionallysubstituted with one or more substituents independently selected fromhydroxy, halogen, —CN, —NO₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆ alkoxy, and C₁-C₆ alkoxy C₁-C₆ alkyl;

R⁶ and R⁷ are each independently selected from hydrogen, hydroxy, andC₁₋₆ alkoxy; or

R⁶ and R⁷ come together to form

R²⁰ is selected from hydrogen and optionally substituted C₁-C₆ alkyl;

R²¹ is selected from optionally substituted C₁-C₆ alkyl, and optionallysubstituted 3 to 7-membered heterocycle;

R²² is selected from hydrogen, optionally substituted C₁-C₆ alkyl,—Si(R²⁴)₃, and —P(═O)(R²⁴)₂;

R²³ is selected from optionally substituted C₁-C₆ alkyl and optionallysubstituted 3 to 7-membered heterocycle;

R²⁴ is optionally substituted C₁-C₆ alkyl;

wherein the substituents on R²⁰, R²¹, R²², R²³, and R²⁴ areindependently selected at each occurrence from:

-   -   halogen, —OR³⁰, —N(R³⁰)₂, —(O—CH₂—(CH₂)_(p))_(n)—W, —SR³⁰,        —N(R³⁰)₂, —C(O)R³⁰, —C(O)N(R³⁰)₂, —N(R³⁰)C(O)R³⁰, —C(O)OR³⁰,        —OC(O)R³⁰, —S(O)R³⁰, —S(O)₂R³⁰, —P(O)(OR³⁰)₂, —OP(O)(OR³⁰)₂,        —NO₂, ═O, ═S, ═N(R³⁰), and —CN;    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, each of which is        optionally substituted with one or more substituents        independently selected from halogen, —OR³⁰, —SR³⁰, —N(R³⁰)₂,        —C(O)R³⁰, —C(O)N(R³⁰)₂, —N(R³⁰)C(O)R³⁰, —C(O)OR³⁰, —OC(O)R³⁰,        —S(O)R³⁰, —S(O)₂R³⁰, —P(O)(OR³⁰)₂, —OP(O)(OR³⁰)₂, —NO₂, ═O, ═S,        ═N(R³⁰), —CN, C₃₋₁₀ carbocycle and 3- to 10-membered        heterocycle; and    -   C₃₋₁₀ carbocycle and 3- to 10-membered heterocycle each of which        is optionally substituted with one or more substituents        independently selected from halogen, —OR³⁰, —SR³⁰, —N(R³⁰)₂,        —C(O)R³⁰, —C(O)N(R³⁰)₂, —N(R³⁰)C(O)R³⁰, —C(O)OR³⁰, —OC(O)R³⁰,        —S(O)R³⁰, —S(O)₂R³⁰, —P(O)(OR³⁰)₂, —OP(O)(OR³⁰)₂, —NO₂, ═O, ═S,        ═N(R³⁰), —CN, C₁₋₆ alkyl, C₁₋₆ alkyl-R³⁰, C₂₋₆ alkenyl, and C₂₋₆        alkynyl;

each p is selected from 1 or 2;

each n is selected from 3 to 7;

each W is selected from hydrogen, —OH, —C₁-C₄ alkyl, and —O(C₁-C₄alkyl);

R³⁰ is independently selected at each occurrence from:

-   -   hydrogen; and    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₂ carbocycle, and        3- to 12-membered heterocycle, each of which is optionally        substituted with one or more substituents independently selected        from halogen, —OH, —OSi(C₁-C₆ alkyl)₃, —CN, —NO₂, —NH₂, ═O, ═S,        C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl, —O—C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl,        C₂₋₁₀ alkynyl, C₃₋₁₂ carbocycle, 3- to 12-membered heterocycle,        and haloalkyl;

z is selected from 0-2;

R′ and R″ are independently selected from hydrogen, halogen, —OR³¹, andC₁₋₃ alkyl optionally substituted with one or more substituentsindependently selected from halogen and —OR³¹;

Ring A is selected from an optionally substituted C₃-C₅ carbocycle andoptionally substituted 3- to 5-membered heterocycle, whereinsubstituents on Ring A are independently selected at each occurrencefrom:

-   -   halogen, —OR³¹, —SR³¹, —N(R³¹)₂, —C(O)R³¹, —C(O)N(R³¹)₂,        N(R³¹)C(O)R³¹, —C(O)OR³¹, —OC(O)R³¹, —S(O)R³¹, —S(O)₂R31,        —P(O)(OR³¹)₂, —OP(O)(OR³¹)₂, —NO₂, ═O, ═S, ═N(R³¹), and —CN;    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, each of which is        optionally substituted with one or more substituents        independently selected from halogen, —OR³¹, —SR³¹, —N(R³¹)₂,        —C(O)R³¹, —C(O)N(R³¹)₂, —N(R³¹)C(O)R³¹, —C(O)OR³¹, —OC(O)R³¹,        —S(O)R³¹, —S(O)₂R³¹, —P(O)(OR³¹)₂, —OP(O)(OR³¹)₂, —NO₂, ═O, ═S,        ═N(R³¹), —CN, C₃₋₁₀ carbocycle and 3- to 10-membered        heterocycle; and    -   C₃₋₁₀ carbocycle and 3- to 10-membered heterocycle each of which        is optionally substituted with one or more substituents        independently selected from halogen, —OR³¹, —SR³¹, —N(R³¹)₂,        —C(O)R³¹, —C(O)N(R³¹)₂, —N(R³¹)C(O)R³¹, —C(O)OR³¹, —OC(O)R³¹,        —S(O)R³¹, —S(O)₂R³¹, —P(O)(OR³¹)₂, —OP(O)(OR³¹)₂, —NO₂, ═O, ═S,        ═N(R³¹), —CN, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl;

R³¹ is independently selected at each occurrence from hydrogen; andC₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₂ carbocycle, and 3- to12-membered heterocycle, each of which is optionally substituted withone or more substituents independently selected from halogen, —OH, —CN,—NO₂, —NH₂, ═O, ═S, C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl, —O—C₁₋₁₀ alkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₂ carbocycle, and 3- to 12-memberedheterocycle; and

R³³ is independently selected at each occurrence from hydroxy, halogen,—CN, —NO₂, ═O, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl, 3- to 10-membered heterocycle, andC₃₋₁₀ carbocycle, wherein the 3- to 10-membered heterocycle and C₃₋₁₀carbocycle are each optionally substituted with one or more substituentsindependently selected from hydroxy, halogen, —CN, —NO₂, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, and C₁-C₆ alkoxyC₁-C₆ alkyl.

In certain embodiments, the compound of Formula (L) is represented byFormula (LA):

(LA) or a salt thereof.

In certain embodiments, the compound of Formula (L) is represented byFormula (LB):

or a salt thereof.

In certain embodiments, the compound of Formula (L) is represented byFormula (LC):

or a salt thereof.

In certain embodiments, the compound of Formula (L) is represented byFormula (LD):

or a salt thereof.

In certain embodiments, the compound of Formula (L) is represented byFormula (LE):

or a salt thereof.

In certain embodiments, the compound of Formula (L) is represented byFormula (LF):

or a salt thereof.

In certain embodiments, the compound of Formula (L) is represented byFormula (LG):

or a salt thereof.

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), z of R⁴, is selected from 0, 1,or 2. In some embodiments, z is selected from 0 and 1. In someembodiments, z is selected from 0 and 2. In some embodiments, z isselected from 1 and 2. In some embodiments, z is selected from anoptionally substituted —CH₂— and optionally substituted —CH₂CH₂—.

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), z is 0 and R⁴ is represented by:

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), z is 1 and R⁴ is represented by:

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), z is 2 and R⁴ is represented by:

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), each R′ and R″ of

is independently selected from hydrogen, halogen, —OR³¹, and C₁₋₃ alkyloptionally substituted with one or more substituents independentlyselected from halogen and —OR³¹. In some embodiments, z is 1 and R′ andR″ are the same substitutent, for example R′ is methyl and R″ is methylor R′ is hydrogen and R″ is hydrogen. In some embodiments, z is 1 and R′and R″ are independently selected from a different substituent, forexample R′ is methyl and R″ is ethyl. In some embodiments, each R′ andR″ are independently selected from hydrogen and C₁₋₃ alkyl. In someembodiments, each R′ and R″ are independently selected from hydrogen,halogen, and —OR³¹. In some embodiments, z is 1 and R′ and R″ are eachhydrogen.

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), Ring A is selected from anoptionally substituted C₃-C₅ carbocycle, such as an optionallysubstituted C₃-C₄ carbocycle, an optionally substituted C₃ carbocycle,an optionally substituted C₄ carbocycle, or an optionally substituted C₅carbocycle. In some embodiments, the optionally substituted carbocycleis unsaturated. In some embodiments, the optionally substitutedcarbocycle is saturated.

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), Ring A is an optionallysubstituted 3- to 5-membered heterocycle, such as an optionallysubstituted 3- to 4-membered heterocycle, an optionally substituted3-membered hetereocycle, an optionally substituted 4-memberedheterocycle or an optionally substituted 5-membered heterocycle. In someembodiments, the optionally substituted heterocycle is unsaturated. Insome embodiments, the optionally substituted heterocycle is saturated.

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), Ring A is selected fromoptionally substituted C₃-C₅ carbocycle and optionally substituted 3- to5-membered heterocycle, wherein each substituent is independentlyselected from: halogen, —OR³¹, —N(R³¹)₂, —C(O)R³¹,—C(O)N(R³¹)₂,N(R³¹)C(O)R³¹, —C(O)OR31, —OC(O)R³¹, —NO₂, and —CN; andC₁₋₃ alkyl optionally substituted with one or more substituentsindependently selected from halogen, —OR³¹, —N(R³¹)₂, —C(O)R³¹,—C(O)N(R³¹)₂, —N(R³¹)C(O)R³¹, —C(O)OR³¹, —OC(O)R³¹, —NO₂, —CN, C₃₋₆carbocycle and 3- to 6-membered heterocycle.

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), Ring A is selected fromoptionally substituted C₃-C₅ carbocycle and optionally substituted 3- to5-membered heterocycle, wherein one or more substituents areindependently selected from: C₁₋₃ alkyl, which is optionally substitutedwith one or more —OR³¹ substituents.

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), Ring A is an optionallysubstituted C₃-C₅ carbocycle selected from:

any one of which is optionally substituted by one or more substituentsindependently selected from halogen, —OR³¹, —N(R³¹)₂, —C(O)R³¹,—C(O)N(R³¹)₂, N(R³¹)C(O)R³¹, —C(O)OR³¹, —OC(O)R³¹, —NO₂, ═O, —CN; andC₁₋₆ alkyl optionally substituted with one or more substituentsindependently selected from halogen, —OR³¹, —N(R³¹)₂, —C(O)R³¹, —NO₂,═O, ═S, —CN, C₃₋₆ carbocycle and 3- to 6-membered heterocycle.

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), R⁴ is

wherein z selected from 1 and 2. In some embodiments, z is selected from0, 1, and 2. In some embodiments, for the compound or salt of Formula(L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), R⁴ is

wherein z selected from 0, 1 and 2. In some embodiments, for thecompound or salt of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or(LG), R⁴ is

wherein z selected from 0, 1 and 2. In some embodiments, for thecompound or salt of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or(LG), R⁴ is selected from:

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), the C₃-carbocycle is optionallysubstituted by one or more substituents independently selected from:halogen, —OR³¹, —N(R³¹)₂, —C(O)R³¹, —C(O)N(R³¹)₂, N(R³¹)C(O)R³¹,—C(O)OR³¹, —OC(O)R³¹, —NO₂, ═O, —CN; and C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, andC₂₋₁₀ alkynyl each of which is optionally substituted with one or moresubstituents independently selected from halogen, —OR³¹, —N(R³¹)₂,—C(O)R³¹, —NO₂, ═O, ═S, —CN, C₃₋₁₀ carbocycle and 3- to 10-memberedheterocycle.

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), the C₃-carbocycle is substitutedby one or more substituents independently selected from: halogen, —OR³¹,—N(R³¹)₂, —C(O)R³¹, —C(O)N(R³¹)₂, N(R³¹)C(O)R³¹, —C(O)OR³¹, —OC(O)R³¹,—NO₂, ═O, —CN; and C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl each ofwhich is optionally substituted with one or more substituentsindependently selected from halogen, —OR³¹, —N(R³¹)₂, —C(O)R³¹, —NO₂,═O, ═S, —CN, C₃₋₁₀ carbocycle and 3- to 10-membered heterocycle.

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), the C₄-carbocycle is optionallysubstituted by one or more substituents independently selected from:halogen, —OR³¹, —N(R³¹)₂, —C(O)R³¹, —C(O)N(R³¹)₂, N(R³¹)C(O)R³¹,—C(O)OR³¹, —OC(O)R³¹, —NO₂, ═O, —CN; and C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, andC₂₋₁₀ alkynyl each of which is optionally substituted with one or moresubstituents independently selected from halogen, —OR³¹, —N(R³¹)₂,—C(O)R³¹, —NO₂, ═O, ═S, —CN, C₃₋₁₀ carbocycle and 3- to 10-memberedheterocycle.

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), the C₄-carbocycle is substitutedby one or more substituents independently selected from: halogen, —OR³¹,—N(R³¹)₂, —C(O)R³¹, —C(O)N(R³¹)₂, N(R³¹)C(O)R³¹, —C(O)OR³¹, —OC(O)R³¹,—NO₂, ═O, —CN; and C₁₋₁₁) alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl eachof which is optionally substituted with one or more substituentsindependently selected from halogen, —OR³¹, —N(R³¹)₂, —C(O)R³¹, —NO₂,═O, ═S, —CN, C₃₋₁₀ carbocycle and 3- to 10-membered heterocycle.

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), the C5-carbocycle is optionallysubstituted by one or more substituents independently selected from:halogen, —OR³¹, —N(R³¹)₂, —C(O)R³¹, —C(O)N(R³¹)₂, N(R³¹)C(O)R³¹,—C(O)OR³¹, —OC(O)R³¹, —NO₂, ═O, —CN; and C₁₋₁₁) alkyl, C₂₋₁₀ alkenyl,and C₂₋₁₀ alkynyl each of which is optionally substituted with one ormore substituents independently selected from halogen, —OR³¹, —N(R³¹)₂,—C(O)R³¹, —NO₂, ═O, ═S, —CN, C₃₋₁₀ carbocycle and 3- to 10-memberedheterocycle.

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), the C5-carbocycle is substitutedby one or more substituents independently selected from: halogen, —OR³¹,—N(R³¹)₂, —C(O)R³¹, —C(O)N(R³¹)₂, N(R³¹)C(O)R³¹, —C(O)OR³¹, —OC(O)R³¹,—NO₂, ═O, —CN; and C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl each ofwhich is optionally substituted with one or more substituentsindependently selected from halogen, —OR³¹, —N(R³¹)₂, —C(O)R³¹, —NO₂,═O, ═S, —CN, C₃₋₁₀ carbocycle and 3- to 10-membered heterocycle.

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), Ring A is an optionallysubstituted 3- to 5-membered heterocycle wherein one or moresubstituents are independently selected from halogen, —OR³¹, —N(R³¹)₂,—C(O)R³¹, —C(O)N(R³¹)₂, N(R³¹)C(O)R³¹, —C(O)OR³¹, —OC(O)R³¹, —NO₂, ═O,—CN; and C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl each of which isoptionally substituted with one or more substituents independentlyselected from halogen, —OR³¹, —N(R³¹)₂, —C(O)R³¹, —NO₂, ═O, ═S, —CN,C₃₋₁₀ carbocycle and 3- to 10-membered heterocycle. In some embodiments,the optionally substituted 3- to 5-membered heterocycle is saturated. Insome embodiments, the optionally substituted 3- to 5-memberedheterocycle is unsaturated.

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), the 3- to 5-membered heterocyclecomprises at least one heteroatom selected from oxygen, nitrogen,sulfur, boron, phoshprous, silicon, selenium, and any combinationthereof. In some embodiments, the 3- to 5-membered heterocycle comprisesat least one heteroatom selected from oxygen, nitrogen, and sulfur.

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), Ring A is a 3-memberedheterocycle wherein the heterocycle comprises one heteroatom selectedfrom oxygen, nitrogen, and sulfur. In some embodiments, Ring A is a3-membered heterocycle optionally substituted by one or moresubstituents independently selected from halogen, —OR³¹, —N(R³¹)₂,—C(O)R³¹, —C(O)N(R³¹)₂, N(R³¹)C(O)R³¹, —C(O)OR³¹, —OC(O)R³¹, —NO₂, ═O,—CN; and C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl each of which isoptionally substituted with one or more substituents independentlyselected from halogen, —OR³¹, —N(R³¹)₂, —C(O)R³¹, —NO₂, ═O, ═S, —CN,C₃₋₁₀ carbocycle and 3- to 10-membered heterocycle.

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), Ring A is a 4-memberedheterocycle optionally substituted by one or more substituentsindependently selected from halogen, —OR³¹, —N(R³¹)₂, —C(O)R³¹,—C(O)N(R³¹)₂, N(R³¹)C(O)R³¹, —C(O)OR³¹, —OC(O)R³¹, —NO₂, ═O, —CN; andC₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl each of which isoptionally substituted with one or more substituents independentlyselected from halogen, —OR³¹, —N(R³¹)₂, —C(O)R³¹, —NO₂, ═O, ═S, —CN,C₃₋₁₀ carbocycle and 3- to 10-membered heterocycle.

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), Ring A is an optionallysubstituted 4-membered heterocycle comprising 1 oxygen atom, wherein the4-membered heterocycle is optionally substituted by one or moresubstituents independently selected from halogen, —OR³¹, —N(R³¹)₂,—C(O)R³¹, —C(O)N(R³¹)₂, N(R³¹)C(O)R³¹, —C(O)OR³¹, —OC(O)R³¹, —NO₂, ═O,—CN; and C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl each of which isoptionally substituted with one or more substituents independentlyselected from halogen, —OR³¹, —N(R³¹)₂, —C(O)R³¹, —NO₂, ═O, ═S, and —CN.In some embodiments, R³¹ of —OR³¹ is independently selected at eachoccurrence from C₁₋₆ alkyl and hydrogen. In some embodiments, R⁴ isselected from:

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), Ring A is a substituted4-membered heterocycle comprising 1 oxygen atom, wherein the 4-memberedheterocycle is substituted by one or more substituents independentlyselected from halogen, —OR³¹, —N(R³¹)₂, —C(O)R³¹, —C(O)N(R³¹)₂,N(R³¹)C(O)R³¹, —C(O)OR³¹, —OC(O)R³¹, —NO₂, ═O, —CN; and C₁₋₁₀ alkyl,C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl each of which is optionally substitutedwith one or more substituents independently selected from halogen,—OR³¹, —N(R³¹)₂, —C(O)R³¹, —NO₂, ═O, ═S, and —CN. In some embodiments,R³¹ of —OR³¹ is independently selected at each occurrence from C₁₋₁₀alkyl and hydrogen. In some embodiments, R⁴ is selected from:

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), the optionally substituted4-membered heterocycle comprises 1 or 2 heteroatoms selected fromnitrogen and sulfur.

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), Ring A is an optionallysubstituted 4-membered heterocycle comprising 1 or 2 nitrogen atoms. Insome embodiments, the optionally substituted 4-membered heterocycle isselected from azetidine, 2,3-dihyroazete, azete, 1,3-diazetidine and1,4-diazetidine, any one of which is optionally substituted by one ormore substituents independently selected from halogen, —OR³¹, —N(R³¹)₂,—C(O)R³¹, —C(O)N(R³¹)₂,N(R³¹)C(O)R³¹, —C(O)OR³¹, —OC(O)R³¹, —NO₂, ═O,—CN; and C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl each of which isoptionally substituted with one or more substituents independentlyselected from halogen, —OR³¹, —N(R³¹)₂, —C(O)R³¹, —NO₂, ═O, ═S, —CN,C₃₋₁₀ carbocycle and 3- to 10-membered heterocycle. In some embodiments,R³¹ of —OR³¹ is independently selected at each occurrence from C₁₋₁₀alkyl and hydrogen.

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), Ring A is an optionallysubstituted 4-membered heterocycle selected from azetidine,1,3-diazetidine and 1,4-diazetidine, any one of which is optionallysubstituted by one or more substituents independently selected fromhalogen, —OR³¹, —N(R³¹)₂, —C(O)R³¹, —C(O)N(R³¹)₂, N(R³¹)C(O)R³¹,—C(O)OR³¹, —OC(O)R³¹, —NO₂, ═O, —CN; and C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, andC₂₋₁₀ alkynyl each of which is optionally substituted with one or moresubstituents independently selected from halogen, —OR³¹, —N(R³¹)₂,—C(O)R³¹, —NO₂, ═O, ═S, —CN, C₃₋₁₀ carbocycle and 3- to 10-memberedheterocycle. In some embodiments, R³¹ of —OR³¹ is independently selectedat each occurrence from C₁₋₁₀ alkyl and hydrogen.

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), Ring A is an optionallysubstituted 4-membered heterocycle selected from 2,3-dihyroazete andazete, any one of which is optionally substituted by one or moresubstituents independently selected from halogen, —OR³¹, —N(R³¹)₂,—C(O)R³¹, —C(O)N(R³¹)₂, N(R³¹)C(O)R³¹, —C(O)OR³¹, —OC(O)R³¹, —NO₂, ═O,—CN; and C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl each of which isoptionally substituted with one or more substituents independentlyselected from halogen, —OR³¹, —N(R³¹)₂, —C(O)R³¹, —NO₂, ═O, ═S, —CN,C₃₋₁₀ carbocycle and 3- to 10-membered heterocycle. In some embodiments,R³¹ of —OR³¹ is independently selected at each occurrence from C₁₋₁₀alkyl and hydrogen.

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), Ring A is an optionallysubstituted azetidine, which is optionally substituted by one or moresubstituents independently selected from C₁₋₁₀ alkyl, each of which isoptionally substituted with one or more substituents independentlyselected from —OR³¹. In some embodiments, R³¹ of —OR³¹is independentlyselected at each occurrence from C₁₋₁₀ alkyl and hydrogen. In someembodiments, R⁴ is selected from:

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is selected from:

In some embodiments, R⁴ is

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), Ring A is an optionallysubstituted 5-membered heterocycle comprising at least one heteroatomselected from nitrogen, oxygen, sulfur, and any combination thereof. Insome embodiments, Ring A is an optionally substituted 5-memberedheterocycle comprising 4 heteroatoms selected from nitrogen, oxygen,sulfur, and any combination thereof.

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), Ring A is an optionallysubstituted 5-membered heterocycle comprising 4 nitrogen atoms. In someembodiments, Ring A is an optionally substituted tetrazole, which isoptionally substituted by one or more substituents independentlyselected from halogen, —OR³¹, —N(R³¹)₂, —C(O)R³¹, —C(O)N(R³¹)₂,N(R³¹)C(O)R³¹, —C(O)OR³¹, —OC(O)R³¹, —NO₂, ═O, —CN; and C₁₋₁₀ alkyl,C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl each of which is optionally substitutedwith one or more substituents independently selected from halogen,—OR31, —N(R³¹)₂, —C(O)R³¹, —NO₂, ═O, ═S, —CN, C₃₋₁₀ carbocycle and 3- to10-membered heterocycle.

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), Ring A is an optionallysubstituted 5-membered heterocycle comprising 3 heteroatoms selectedfrom nitrogen, oxygen, sulfur, and any combination thereof.

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), Ring A is an optionallysubstituted 5-membered heterocycle comprising 3 heteroatoms selectedfrom nitrogen, oxygen, and sulfur, wherein the optionally substituted5-membered heterocycle is selected from 1,2,4-triazole, 1,2,3-triazole,1,2,5-oxadiazole, 1,2,3-oxadiazole, 1,3,4-thiadiazole, and1,2,5-thiadiazole, any one of which is optionally substituted by one ormore substituents independently selected from halogen, —OR31, —N(R³¹)₂,—C(O)R³¹, —C(O)N(R³¹)₂, N(R³¹)C(O)R³¹, —C(O)OR³¹, —OC(O)R³¹, —NO₂, ═O,—CN; and C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl each of which isoptionally substituted with one or more substituents independentlyselected from halogen, —OR³¹, —N(R³¹)₂, —C(O)R³¹, —NO₂, ═O, ═S, —CN,C₃₋₁₀ carbocycle and 3- to 10-membered heterocycle.

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), Ring A is an optionallysubstituted 5-membered heterocycle comprising 2 heteroatoms selectedfrom nitrogen, oxygen, and sulfur, wherein the optionally substituted5-membered heterocycle is selected from pyrazolidine, imidazolidine,2-pyrazoline, 2-imidazoline, pyrazole, imidazole, 1,3-dioxolane,oxazole, isoxazole, thiazole, isothiazole, 1,2-oxathiolane, and1,3-oxathiolane, any one of which is optionally substituted by one ormore substituents independently selected from halogen, —OR³¹, —N(R³¹)₂,—C(O)R³¹, —C(O)N(R³¹)₂, N(R³¹)C(O)R³¹, —C(O)OR³¹, —OC(O)R³¹, —NO₂, ═O,—CN; and C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl each of which isoptionally substituted with one or more substituents independentlyselected from halogen, —OR³¹, —N(R³¹)₂, —C(O)R³¹, —NO₂, ═O, ═S, —CN,C₃₋₁₀ carbocycle and 3- to 10-membered heterocycle.

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), Ring A is a substituted5-membered heterocycle comprising 2 oxygen atoms, wherein the optionallysubstituted 5-membered heterocycle is selected at each occurrence fromfrom halogen, —OR³¹, —N(R³¹)₂, —C(O)R³¹, —C(O)N(R³¹)₂, N(R³¹)C(O)R³¹,—C(O)OR31, —OC(O)R³¹, —NO₂, ═O, —CN; and C₂₋₁₀ alkyl, C₂₋₁₀ alkenyl, andC₂₋₁₀ alkynyl each of which is optionally substituted with one or moresubstituents independently selected from halogen, —OR³¹, —N(R³¹)₂,—C(O)R³¹, —NO₂, ═O, ═S, —CN, C₃₋₁₀ carbocycle and 3- to 10-memberedheterocycle.

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), when R¹ is hydroxy, R⁴ is not

In some embodiments, R⁴ is not

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), Ring A is an optionallysubstituted 5-membered heterocycle comprising 1 heteroatom selected fromnitrogen, oxygen, and sulfur. In some embodiments, Ring A is selectedfrom pyrrolidine, 3-pyrroline, 2-pyrroline, 2H-pyrrole, 1H-pyrrole,tetrahydrofuran, furan, tetrahydrothiophene, and thiophene, any one ofwhich is optionally substituted by one or more substituentsindependently selected from halogen, —OR³¹, —N(R³¹)₂, —C(O)R³¹,—C(O)N(R³¹)₂, N(R³¹)C(O)R³¹, —C(O)OR³¹, —OC(O)R³¹, —NO₂, ═O, —CN; andC₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl each of which isoptionally substituted with one or more substituents independentlyselected from halogen, —OR³¹, —N(R³¹)₂, —C(O)R³¹, —NO₂, ═O, ═S, —CN,C₃₋₁₀ carbocycle and 3- to 10-membered heterocycle.

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), Ring A is an optionallysubstituted 5-membered heterocycle comprising 1 oxygen atom, wherein theoptionally substituted 5-membered heterocycle is selected fromtetrahydrofuran and furan, any one of which is optionally substituted byone or more substituents independently selected from halogen, —OR³¹,—N(R³¹)₂, —C(O)R³¹, —C(O)N(R³¹)₂, N(R³¹)C(O)R³¹, —C(O)OR³¹, —OC(O)R³¹,—NO₂, ═O, —CN; and C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl each ofwhich is optionally substituted with one or more substituentsindependently selected from halogen, —OR³¹, —N(R³¹)₂, —C(O)R³¹, —NO₂,═O, ═S, —CN, C₃₋₁₀ carbocycle and 3- to 10-membered heterocycle.

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), Ring A is an optionallysubstituted 5-membered heterocycle is selected from tetrahydrofuran andfuran which is optionally substituted by one or more substituentsindependently selected from halogen, —OR³¹, and C₁₋₁₀ alkyl. In someembodiments, the optionally substituted 5-membered heterocycle istetrahydrofuran which is optionally substituted by one or moresubstituents independently selected from halogen, —OR³¹, and C₁₋₁₀alkyl. In some embodiments, R³¹ of —OR³¹ is selected from hydrogen andC₁₋₁₀ alkyl. In some embodiments, R⁴ is selected from

In some embodiments, R⁴ is selected from

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), Ring A is an optionallysubstituted 5-membered heterocycle comprising 1 nitrogen atom, whereinthe optionally substituted 5-membered heterocycle is selected frompyrrolidine, 3-pyrroline, 2-pyrroline, 2H-pyrrole, and 1H-pyrrole, anyone of which is optionally substituted by one or more substituentsindependently selected from halogen, —OR³¹, —N(R³¹)₂, —C(O)R³¹,—C(O)N(R³¹)₂, N(R³¹)C(O)R³¹, —C(O)OR³¹, —OC(O)R³¹, —NO₂, ═O, —CN; andC₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl each of which isoptionally substituted with one or more substituents independentlyselected from halogen, —OR³¹, —N(R³¹)₂, —C(O)R31, —NO₂, ═O, ═S, —CN,C₃₋₁₀ carbocycle and 3- to 10-membered heterocycle.

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), the optionally substituted5-membered heterocycle is is selected from pyrrolidine, 3-pyrroline,2-pyrroline, 2H-pyrrole, and 1H-pyrrole, any one of which is optionallysubstituted by one or more substituents independently selected fromhalogen, —OR³¹; and C₁₋₁₀ alkyl, each of which is optionally substitutedwith one or more substituents independently selected from OR³¹. In someembodiments, R³¹ of —OR³¹ is independently selected at each occurrencefrom C₁₋₁₀ alkyl and hydrogen. In some embodiments, R⁴ is selected from:

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), Ring A is an optionallysubstituted 5-membered heterocycle comprising 1 sulfur atom, wherein theoptionally substituted 5-membered heterocycle is selected fromtetrahydrothiophene and thiophene, any one of which is optionallysubstituted by one or more substituents independently selected fromhalogen, —OR³¹, —N(R³¹)₂, —C(O)R³¹, —C(O)N(R³¹)₂, N(R³¹)C(O)R³¹,—C(O)OR³¹, —OC(O)R³¹, —NO₂, ═O, —CN; and C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, andC₂₋₁₀ alkynyl each of which is optionally substituted with one or moresubstituents independently selected from halogen, —OR³¹, —N(R³¹)₂,—C(O)R³¹, —NO₂, ═O, ═S, —CN, C₃₋₁₀ carbocycle and 3- to 10-memberedheterocycle.

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), the optionally substituted5-membered heterocycle is tetrahydrothiophene which is optionallysubstituted by one or more substituents independently selected from—OR³¹, ═O, and C₁₋₁₀ alkyl. In some embodiments, R⁴ is selected from

In some embodiments, R⁴ is from

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), R⁴ is selected from is selectedfrom

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), R² is selected from hydrogen andan optionally substituted C₁-C₆ alkoxy group, wherein substituents areindependently selected at each occurrence from hydroxy, halogen, —CN,—NO₂, and C₁-C₆ alkoxy. In some embodiments, R² is selected fromhydrogen and an optionally substituted C₁-C₆ alkoxy, whereinsubstituents are independently selected at each occurrence from hydroxy,halogen, —NO₂, and C₁-C₆ alkoxy.

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), R² is selected from hydrogen andC₁-C₆ alkoxy. In some embodiments, R² is selected from hydrogen and—OMe. In some embodiments, R² is —OMe.

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), R³ is selected from hydrogen andan optionally substituted C₁-C₆ alkoxy, wherein the substituents areindependently selected at each occurrence from hydroxy and C₁-C₆ alkoxy.In some embodiments, R³ is selected from hydrogen and C₁-C₆ alkoxy.

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), R³ is selected from C₁-C₆ alkoxy.In some embodiments, R³ is —OMe.

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), R⁵ is selected from hydrogen,hydroxy, and an optionally substituted C₁-C₆ alkoxy group, whereinsubstituents are independently selected at each occurrence from hydroxy,halogen, —CN, —NO₂, and C₁-C₆ alkoxy.

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), R⁵ is, hydroxy.

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), R⁶ and R⁷ are each independentlyselected from hydrogen and hydroxy. In some embodiments, R⁶ and R⁷ areeach hydrogen. In some embodiments, R⁶ is hydrogen and R⁷ hydroxy. Insome embodiments, R⁶ and R⁷ come together to form

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), R¹ is selected from

and optionally substituted 3- to 10-membered heterocycle. In someembodiments, for the compound or salt of Formula (L), (LA), (LB), (LC),(LD), (LE), (LF), or (LG), R¹ is selected from

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), R¹ is selected from hydroxy.

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), R¹ is an optionally substituted3- to 10-membered heterocycle. In some embodiments, the optionallysubstituted heterocycle is 3-, 4-, 5-, 6-, 7-, 8-, 9-, or a 10-memberedheterocycle. In some embodiments, the optionally substituted 3- to10-membered heterocycle is a 3- or 4-membered heterocycle, a 5- or6-membered heterocycle, a 7- or 8-membered heterocycle, or a 9- or10-membered heterocycle.

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), R¹ is an optionally substituted5- to 6-membered heterocycle comprising at least 1 heteroatom that isselected from oxygen, nitrogen, sulfur, boron, phoshprous, silicon,selenium, and any combination thereof. In some embodiments, theoptionally substituted 5- to 6-membered heterocycle comprises at least 1heteroatom that is selected from oxygen, nitrogen, sulfur, and anycombination thereof.

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), the optionally substituted 5- to6-membered heterocycle of R¹ comprises at least 1 heteroatom that isselected from nitrogen. In some embodiments, the optionally substituted5- to 6-membered heterocycle of R¹ is selected from

any of which is optionally substituted with one or more substituentsindependently selected from: hydroxy, halogen, —CN, —NO₂, ═O, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, 3- to10-membered heterocycle, and C₃₋₁₀ carbocycle, wherein the 3- to10-membered heterocycle and C₃₋₁₀ carbocycle are each optionallysubstituted with one or more substituents independently selected fromhydroxy, halogen, —CN, —NO₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆hydroxyalkyl, and C₁-C₆ alkoxy. In some embodiments, the one or moresubstituents are independently hydroxy, ═O, C₁-C₆ alkyl, 3- to8-membered heterocycle, and C₃₋₈ carbocycle, wherein the 3- to8-membered heterocycle and C₃₋₈ carbocycle are each optionallysubstituted with one or more substituents independently selected fromhydroxy, halogen, —CN, —NO₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆hydroxyalkyl, and C₁-C₆ alkoxy.

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), R¹ is

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), R²² of R¹ is selected fromhydrogen, optionally substituted C₁-C₆ alkyl, and —P(═O)(R²⁴)₂.

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), R²² of R¹ is hydrogen.

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), R²² of R¹ is —P(═O)(R²⁴)₂, andR²⁴ is selected from optionally substituted C₁₋₁₀ alkyl. In someembodiments, R¹ is

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), R²² of R¹ is C₁-C₆ alkyloptionally substituted with one or more substituents selected from—N(R³⁰)₂, —(O—CH₂—(CH₂)_(p))_(n)—W, —OR³⁰, optionally substituted C₃₋₁₀carbocycle, and optionally substituted 3- to 10-membered heterocycle,and R³⁰ is selected from hydrogen and optionally substituted C₁₋₁₀alkyl. In some embodiments, R²² of R¹, is C₁-C₆ alkyl substituted withone or more substituents selected from —N(R³⁰)₂,—(O—CH₂—(CH₂)_(p))_(n)—W, and —OR³⁰.

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), R²² of R¹ is C₁-C₆ alkylsubstituted with one or more substituents selected from —N(R³⁰)₂. Insome embodiments, R¹ is

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), R²² of R¹ is C₁-C₆ alkylsubstituted with one or more substituents selected from—(O—CH₂—(CH₂)_(p))_(n)—W, wherein n is 1 to 1000. In some embodiments, nis 1 to 800. In some embodiments, n is 1 to 500. In some embodiments, nis 1 to 300. In some embodiments, n is 1 to 100. In some embodiments, nis 1 to 50. In some embodiments, n is 1 to 25. In some embodiments, n is3 to 1000. In some embodiments, n is 10 to 1000. In some embodiments, nis 50 to 1000. In some embodiments, n is 100 to 1000. In someembodiments, n is 200 to 1000. In some embodiments, n is 500 to 1000. Insome embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20, 25, or 100. In some embodiments, p is 1 to 1000.In some embodiments, p is 1 to 800. In some embodiments, p is 1 to 500.In some embodiments, p is 1 to 300. In some embodiments, p is 1 to 100.In some embodiments, p is 1 to 50. In some embodiments, p is 1 to 25. Insome embodiments, p is 3 to 1000. In some embodiments, p is 10 to 1000.In some embodiments, p is 50 to 1000. In some embodiments, p is 100 to1000. In some embodiments, p is 200 to 1000. In some embodiments, p is500 to 1000. In some embodiments, p is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, or 100.

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), R²² of R¹is C₁-C₆ alkylsubstituted with one or more substituents selected from—(O—CH₂—(CH₂)_(p))_(n)—W, and —OR³⁰. In some embodiments, R¹ is selectedfrom:

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), R²² of R¹ is C₁-C₆ alkylsubstituted with substituents selected from an optionally substitutedC₃₋₁₀ carbocycle. In some embodiments, the optionally substituted C₃₋₁₀carbocycle is selected from a C₃₋₆ carbocycle. In certain embodiments,the C₃₋₆ carbocycle is unsaturated. In certain embodiments, the C₃₋₆carbocycle is saturated. In some embodiments, the optionally substitutedC₃₋₆ carbocycle is selected from

In some embodiments, R²² of R¹ is C₁-C₆ alkyl substituted with phenyl.In some embodiments, R¹ is selected from:

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), R²² of R¹ is C₁-C₆ alkylsubstituted with one or more substituents selected from an optionallysubstituted 3- to 6-membered heterocycle. In some embodiments, theoptionally substituted 3- to 6-membered heterocycle comprises at leastone heteroatom selected from N, O, S, and any combination thereof.

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), R²² of R¹ is C₁-C₆ alkylsubstituted with one or more substituents selected from an optionallysubstituted 3- to 6-membered heterocycle wherein the optionallysubstituted 3- to 6-membered heterocycle comprises at least oneheteroatom selected from N and O. In some embodiments, the 3- to6-membered heterocycle is substituted with one or more substituentsselected from optionally substituted C₁₋₆ alkyl and —OR³⁰. In someembodiments, R¹ is selected from:

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), R¹ is selected from:

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), R¹ is selected from:

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), R¹ is

In some embodiments, R²⁰ of R¹ is selected from hydrogen and optionallysubstituted C₁-C₃ alkyl. In some embodiments, R²¹ of R¹ is selected fromhydrogen and optionally substituted C₁-C₃ alkyl. In some embodiments,R²¹ of R¹ is an optionally substituted C₁₋₁₀ alkyl. In some embodiments,R²¹ of R¹ is C₁₋₁₀ alkyl substituted with one or more substituentsselected from —OR³⁰, —N(R³⁰)₂, —(O—CH₂—(CH₂)_(p))_(n)—W, optionallysubstituted C₃₋₁₀ carbocycle and optionally substituted 3- to10-membered heterocycle. In some embodiments, R¹ is selected from:

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), R¹ is

wherein R²¹ of R¹ is an optionally substituted 3- to 7-memberedheterocycle. In some embodiments, the 3- to 7-membered heterocycle issubstituted with one or more substituents selected from —OR³⁰ andoptionally substituted C₁₋₁₀ alkyl. In some embodiments, R¹ is selectedfrom:

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), R¹ is

In some embodiments, R²³ of R¹ is an optionally substituted C₁-C₆ alkyl.In some embodiments, C₁-C₆ alkyl is substituted with one or moresubstituents selected from —OR³⁰, —N(R³⁰)₂, optionally substituted C₁₋₁₀alkyl, optionally substituted C₃₋₁₀ carbocycle and 3- to 10-memberedheterocycle. In some embodiments, R¹ is selected from:

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), R²³ of R¹ is an optionallysubstituted 3- to 7-membered heterocycle. In some embodiments, the 3- to7-membered heterocycle is substituted with one or more substituentsselected from optionally substituted C₁₋₁₀ alkyl. In some embodiments,R¹ is

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), R¹ is selected from:

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), R¹ is selected from:

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), R¹ is selected from:

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), R¹ is selected from:

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), R¹ is selected from:

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), R¹ is selected from: —OH and

In some cases, R¹ is

and R²² is selected from optionally substituted C₁-C₆ alkyl, preferablyan optionally substituted C₂₋₄ alkyl. In some cases, R¹ is

and R²² is selected from substituted C₁-C₆ alkyl, preferably asubstituted C₂₋₄ alkyl. In some cases, the substituents on R²² areindependently selected from —OR³⁰, —(O—CH₂—(CH₂)_(p))_(n)—W, —S(O)R³⁰,—S(O)₂R³⁰, ═O, ═S, ═N(R³⁰), and —CN. In some cases, the optionalsubstituents on R²² are independently selected from —OR³⁰, —S(O)₂R³⁰,and ═O. In some cases, the optional substituents on R²² areindependently selected from —OR³⁰, and —S(O)₂R³⁰. In some cases, R³⁰ of—OR³⁰ and —S(O)₂R³⁰, are independently selected from hydrogen and C₁₋₁₀alkyl, wherein the C₁₋₁₀ alkyl is optionally substituted with one ormore substituents independently selected from halogen, —OH, —CN, —NO₂,—NH₂, ═O, ═S, —C₁₋₁₀ haloalkyl, —O—C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₁₀ carbocycle, and 3- to 10-membered heterocycle. In somecases, R³⁰ of —OR³⁰ and —S(O)₂R³⁰ is independently selected at eachoccurrence from hydrogen and C₁₋₁₀ alkyl.

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), R¹ is selected from

In some cases, R¹ is selected from

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), R′ and R″ are independentlyselected at each occurrence from hydrogen.

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), Ring A is selected from anoptionally substituted C₃-C₅ carbocycle and optionally substituted 4- to5-membered heterocycle, wherein optional substituents on Ring A areindependently selected at each occurrence from halogen, ═O, —OH, —O—C₁₋₃alkyl, and —CN. In some cases, Ring A is selected from an optionallysubstituted saturated C₃-C₅ carbocycle and optionally substitutedsaturated 4- to 5-membered heterocycle, wherein optional substituents onRing A are independently selected at each occurrence from halogen, ═O,—OH, —O—C₁₋₃ alkyl, and —CN. In some cases, the compound or salt ofFormula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), the 4- to5-membered heterocycle includes at least one heteroatom selected fromoxygen and sulfur.

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), R⁴ is selected from

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), R⁴ is selected from

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), R⁴ is selected from

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), Ring A is selected from anunsubstituted C₃-C₅ carbocycle and optionally substituted 4- to5-membered heterocycle, wherein optional substituents on the 4- to5-membered heterocyle are independently selected at each occurrence fromhalogen, ═O, —OH, —O—C₁₋₃ alkyl, and —CN.

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), R⁴ is selected from

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), Ring A is selected from anoptionally substituted C₃-C₅ carbocycle.

In some embodiments, for the compound or salt of Formula (L), (LA),(LB), (LC), (LD), (LE), (LF), or (LG), Ring A is selected from anunsubstituted C₃-C₅ carbocycle. In some cases, z is selected from 0and 1. In some cases, R⁴ is selected from

In some embodiments, the compound or salt of Formula (L), (LA), (LB),(LC), (LD), (LE), (LF), or (LG)is selected from:

Compound Groups 1, 2, and 3

Chemical entities having carbon-carbon double bonds or carbon-nitrogendouble bonds may exist in Z- or E- form (or cis- or trans- form).Furthermore, some chemical entities may exist in various tautomericforms. Unless otherwise specified, compounds described herein areintended to include all Z-, E- and tautomeric forms as well.

“Isomers” are different compounds that have the same molecular formula.“Stereoisomers” are isomers that differ only in the way the atoms arearranged in space. “Enantiomers” are a pair of stereoisomers that arenon-superimposable mirror images of each other. A 1:1 mixture of a pairof enantiomers is a “racemic” mixture. The term “(±)” is used todesignate a racemic mixture where appropriate. “Diastereoisomers” or“diastereomers” are stereoisomers that have at least two asymmetricatoms but are not minor images of each other. The absolutestereochemistry is specified according to the Cahn-Ingold-Prelog R-Ssystem. When a compound is a pure enantiomer, the stereochemistry ateach chiral carbon can be specified by either R or S. Resolved compoundswhose absolute configuration is unknown can be designated (+) or (−)depending on the direction (dextro- or levorotatory) in which theyrotate plane polarized light at the wavelength of the sodium D line.Certain compounds described herein contain one or more asymmetriccenters and can thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms, the asymmetric centers of which can be defined, interms of absolute stereochemistry, as (R)- or (S)-. The present chemicalentities, pharmaceutical compositions and methods are meant to includeall such possible stereoisomers, including racemic mixtures, opticallypure forms, mixtures of diastereomers and intermediate mixtures.Optically active (R)- and (S)-isomers can be prepared using chiralsynthons or chiral reagents, or resolved using conventional techniques.The optical activity of a compound can be analyzed via any suitablemethod, including but not limited to chiral chromatography andpolarimetry, and the degree of predominance of one stereoisomer over theother isomer can be determined.

When stereochemistry is not specified, molecules with stereocentersdescribed herein include isomers, such as enantiomers and diastereomers,mixtures of enantiomers, including racemates, mixtures of diastereomers,and other mixtures thereof, to the extent they can be made by one ofordinary skill in the art by routine experimentation. In certainembodiments, the single enantiomers or diastereomers, i.e., opticallyactive forms, can be obtained by asymmetric synthesis or by resolutionof the racemates or mixtures of diastereomers. Resolution of theracemates or mixtures of diastereomers, if possible, can beaccomplished, for example, by conventional methods such ascrystallization in the presence of a resolving agent, or chromatography,using, for example, a chiral high-pressure liquid chromatography (HPLC)column. Furthermore, a mixture of two enantiomers enriched in one of thetwo can be purified to provide further optically enriched form of themajor enantiomer by recrystallization and/or trituration.

In certain embodiments, compositions of the disclosure may comprise twoor more enantiomers or diatereomers of a compound wherein a singleenantiomer or diastereomer accounts for at least about 70% by weight, atleast about 80% by weight, at least about 90% by weight, at least about98% by weight, or at least about 99% by weight or more of the totalweight of all stereoisomers. Methods of producing substantially pureenantiomers are well known to those of skill in the art. For example, asingle stereoisomer, e.g., an enantiomer, substantially free of itsstereoisomer may be obtained by resolution of the racemic mixture usinga method such as formation of diastereomers using optically activeresolving agents (Stereochemistry of Carbon Compounds, (1962) by E. L.Eliel, McGraw Hill; Lochmuller (1975) J. Chromatogr., 113(3): 283-302).Racemic mixtures of chiral compounds can be separated and isolated byany suitable method, including, but not limited to: (1) formation ofionic, diastereomeric salts with chiral compounds and separation byfractional crystallization or other methods, (2) formation ofdiastereomeric compounds with chiral derivatizing reagents, separationof the diastereomers, and conversion to the pure stereoisomers, and (3)separation of the substantially pure or enriched stereoisomers directlyunder chiral conditions. Another approach for separation of theenantiomers is to use a Diacel chiral column and elution using anorganic mobile phase such as done by Chiral Technologies(www.chiraltech.com) on a fee for service basis.

A “tautomer” refers to a molecule wherein a proton shift from one atomof a molecule to another atom of the same molecule is possible. Thecompounds presented herein, in certain embodiments, exist as tautomers.In circumstances where tautomerization is possible, a chemicalequilibrium of the tautomers will exist. The exact ratio of thetautomers depends on several factors, including physical state,temperature, solvent, and pH. Some examples of tautomeric equilibriuminclude:

The compounds disclosed herein, in some embodiments, are used indifferent enriched isotopic forms, e.g., enriched in the content of ²H,³H, ¹¹C, ¹³C and/or ¹⁴C. In one particular embodiment, the compound isdeuterated in at least one position. Such deuterated forms can be madeby the procedure described in U.S. Pat. Nos. 5,846,514 and 6,334,997. Asdescribed in U.S. Pat. Nos. 5,846,514 and 6,334,997, deuteration canimprove the metabolic stability and or efficacy, thus increasing theduration of action of drugs.

Unless otherwise stated, compounds described herein are intended toinclude compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of a hydrogen by a deuterium ortritium, or the replacement of a carbon by ¹³C- or ¹⁴C-enriched carbonare within the scope of the present disclosure.

The compounds of the present disclosure optionally contain unnaturalproportions of atomic isotopes at one or more atoms that constitute suchcompounds. For example, the compounds may be labeled with isotopes, suchas for example, deuterium (²H), tritium (³H), iodine-125 (¹²⁵I) orcarbon-14 (¹⁴C). Isotopic substitution with ²H, ¹¹C, ¹³C, ¹⁴C, ¹⁵C, ¹²N,¹³N, ¹⁵N, ¹⁶N, ¹⁶O, ¹⁷O, ¹⁴F, ¹⁵F, ¹⁶F, ¹⁷F, ¹⁸F, ³³S, ³⁴S, ³⁵S, ³⁶S,³⁵Cl, ³⁷Cl, ⁷⁹Br, ⁸¹Br, and ¹²⁵I are all contemplated. All isotopicvariations of the compounds of the present invention, whetherradioactive or not, are encompassed within the scope of the presentinvention.

In certain embodiments, the compounds disclosed herein have some or allof the ¹H atoms replaced with ²H atoms. The methods of synthesis fordeuterium-containing compounds are known in the art and include, by wayof non-limiting example only, the following synthetic methods.

Deuterium substituted compounds are synthesized using various methodssuch as described in: Dean, Dennis C.; Editor. Recent Advances in theSynthesis and Applications of Radiolabeled Compounds for Drug Discoveryand Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp;George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compoundsvia Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21;and Evans, E. Anthony. Synthesis of radiolabeled compounds, J.Radioanal. Chem., 1981, 64(1-2), 9-32.

Deuterated starting materials are readily available and are subjected tothe synthetic methods described herein to provide for the synthesis ofdeuterium-containing compounds. Large numbers of deuterium-containingreagents and building blocks are available commercially from chemicalvendors, such as Aldrich Chemical Co.

Compounds of the present invention also include crystalline andamorphous forms of those compounds, pharmaceutically acceptable salts,and active metabolites of these compounds having the same type ofactivity, including, for example, polymorphs, pseudopolymorphs,solvates, hydrates, unsolvated polymorphs (including anhydrates),conformational polymorphs, and amorphous forms of the compounds, as wellas mixtures thereof.

Included in the present disclosure are salts, particularlypharmaceutically acceptable salts, of the compounds described herein.The compounds of the present disclosure that possess a sufficientlyacidic, a sufficiently basic, or both functional groups, can react withany of a number of inorganic bases, and inorganic and organic acids, toform a salt. Alternatively, compounds that are inherently charged, suchas those with a quaternary nitrogen, can form a salt with an appropriatecounterion, e.g., a halide such as bromide, chloride, or fluoride,particularly bromide.

The methods and compositions described herein include the use ofamorphous forms as well as crystalline forms (also known as polymorphs).The compounds described herein may be in the form of pharmaceuticallyacceptable salts. As well, in some embodiments, active metabolites ofthese compounds having the same type of activity are included in thescope of the present disclosure. In addition, the compounds describedherein can exist in unsolvated as well as solvated forms withpharmaceutically acceptable solvents such as water, ethanol, and thelike. The solvated forms of the compounds presented herein are alsoconsidered to be disclosed herein.

In certain embodiments, compounds or salts of the compounds may beprodrugs, e.g., wherein a hydroxyl in the parent compound is presentedas an ester or a carbonate, or carboxylic acid present in the parentcompound is presented as an ester. The term “prodrug” is intended toencompass compounds which, under physiologic conditions, are convertedinto pharmaceutical agents of the present disclosure. One method formaking a prodrug is to include one or more selected moieties which arehydrolyzed under physiologic conditions to reveal the desired molecule.In other embodiments, the prodrug is converted by an enzymatic activityof the host animal such as specific target cells in the host animal. Forexample, esters or carbonates (e.g., esters or carbonates of alcohols orcarboxylic acids and esters of phosphonic acids) are preferred prodrugsof the present disclosure.

Prodrugs are often useful because, in some situations, they may beeasier to administer than the parent drug. They may, for instance, bebioavailable by oral administration whereas the parent is not. Prodrugsmay help enhance the cell permeability of a compound relative to theparent drug. The prodrug may also have improved solubility inpharmaceutical compositions over the parent drug. Prodrugs may bedesigned as reversible drug derivatives, for use as modifiers to enhancedrug transport to site-specific tissues or to increase drug residenceinside of a cell.

In some embodiments, the design of a prodrug increases the lipophilicityof the pharmaceutical agent. In some embodiments, the design of aprodrug increases the effective water solubility. See, e.g., Fedorak etal., Am. J. Physiol., 269:G210-218 (1995); McLoed et al., Gastroenterol,106:405-413 (1994); Hochhaus et al., Biomed. Chrom., 6:283-286 (1992);J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J.Larsen et al., Int. J. Pharmaceutics, 47, 103 (1988); Sinkula et al., J.Pharm. Sci., 64:181-210 (1975); T. Higuchi and V. Stella, Pro-drugs asNovel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series; andEdward B. Roche, Bioreversible Carriers in Drug Design, AmericanPharmaceutical Association and Pergamon Press, 1987, all incorporatedherein for such disclosure). According to another embodiment, thepresent disclosure provides methods of producing the above-definedcompounds. The compounds may be synthesized using conventionaltechniques. Advantageously, these compounds are conveniently synthesizedfrom readily available starting materials.

Synthetic chemistry transformations and methodologies useful insynthesizing the compounds described herein are known in the art andinclude, for example, those described in R. Larock, ComprehensiveOrganic Transformations (1989); T. W. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, 2d. Ed. (1991); L. Fieser and M.Fieser, Fieser and Fieser's Reagents for Organic Synthesis (1994); andL. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (1995).

Pharmaceutical Formulations for Compounds of Groups 1, 2, and 3

A compound or salt of any one of the Formulas or sub Formulas describedherein (e.g., Formula (I), Formula (X), Formula (L), ect.,) may beformulated in any suitable pharmaceutical formulation. A pharmaceuticalformulation of the present disclosure typically contains an activeingredient (e.g., compound or salt of any one of the Formulas describedherein) and one or more pharmaceutically acceptable excipients orcarriers, including but not limited to: inert solid diluents andfillers, diluents, sterile aqueous solution and various organicsolvents, permeation enhancers, antioxidents, solubilizers, andadjuvants.

In certain embodiments, a compound or salt of any one of the Formulas orsub Formulas described herein (e.g., Formula (I) of the first aspect,Formula (X) of the second aspect, Formula (L) of the third aspect,ect.,) is formulated with an agent that inhibits degradation of thecompound or salt. In certain embodiments, the compound or salt isformulated with one or more antioxidants. Acceptable antioxidantsinclude, but are not limited to, citric acid, d,I-a-tocopherol, BHA,BHT, monothioglycerol, ascorbyl palmitate, ascorbic acid, and propylgallate. In certain embodiments, the formulation contains from 0.1 to30%, from 0.5 to 25%, from 1 to 20%, from 5 to 15%, or from 7 to 12%(wt/wt) CCI-779, from 0.5 to 50%, from 1 to 40%, from 5 to 35%, from 10to 25%, or from 15 to 20% (wt/wt) water soluble polymer, from 0.5 to10%, 1 to 8%, or 3 to 5% (wt/wt) surfactant, and from 0.001% to 1%,0.01% to 1%, or 0.1% to 0.5% (wt/wt) antioxidant. In certainembodiments, the antioxidants of the formulations of this invention willbe used in concentrations ranging from 0.001% to 3% wt/wt.

In certain embodiments, a compound or salt of any one of the Formulas orsub Formulas described herein (e.g., Formula (I) of the first aspect,Formula (X) of the second aspect, Formula (L) of the third aspect,ect.,) is formulated with a pH modifying agent to maintain a pH of about4 to about 6. Acceptable pH modifying agents include, but are notlimited to citric acid, sodium citrate, dilute HCl, and other mild acidsor bases capable of buffering a solution containing a compound or a saltof the discloure to a pH in the range of about 4 to about 6.

In certain embodiments, a compound or salt of any one of the Formulas orsub Formulas described herein (e.g., Formula (I) of the first aspect,Formula (X) of the second aspect, Formula (L) of the third aspect,ect.,) is formulated with a chelating agent or other material capable ofbinding metal ions, such as ethylene diamine tetra acetic acid (EDTA)and its salts are capable of enhancing the stability of a compound orsalt of any one of the Formulas described herein (e.g., Formula (I),Formula (X), Formula (L), ect.,).

Pharmaceutical formulations may be provided in any suitable form, whichmay depend on the route of administration. In some embodiments, thepharmaceutical composition disclosed herein can be formulated in dosageform for administration to a subject. In some embodiments, thepharmaceutical composition is formulated for oral, intravenous,intraarterial, aerosol, parenteral, buccal, topical, transdermal,rectal, intramuscular, subcutaneous, intraosseous, intranasal,intrapulmonary, transmucosal, inhalation, and/or intraperitonealadministration. In some embodiments, the dosage form is formulated fororal administration. For example, the pharmaceutical composition can beformulated in the form of a pill, a tablet, a capsule, an inhaler, aliquid suspension, a liquid emulsion, a gel, or a powder. In someembodiments, the pharmaceutical composition can be formulated as a unitdosage in liquid, gel, semi-liquid, semi-solid, or solid form.

The amount of a compound or salt of any one of the Formulas or subFormulas described herein (e.g., Formula (I), Formula (X), Formula (L),ect.,) will be dependent on the mammal being treated, the severity ofthe disorder or condition, the rate of administration, the dispositionof the compound or salt of any one of the Formulas or sub Formulasdescribed herein (e.g., Formula (I), Formula (X), Formula (L), ect.,)and the discretion of the prescribing physician.

In some embodiments, pharmaceutically acceptable carriers of a compoundor salt of any one of the Formulas or sub Formulas described herein(e.g., Formula (I), Formula (X), Formula (L),Formula (I), Formula (X),Formula (L), ect.,) can include a physiologically acceptable compoundthat is an antioxidant.

In some embodiments, the disclosure provides a pharmaceuticalcomposition for oral administration containing at least one compound orsalt of any one of the Formulas or sub Formulas described herein (e.g.,Formula (I), Formula (X), Formula (L), ect.,) and a pharmaceuticalexcipient suitable for oral administration. The composition may be inthe form of a solid, liquid, gel, semi-liquid, or semi-solid. In someembodiments, the composition further comprises a second agent.

Pharmaceutical compositions of the disclosure suitable for oraladministration can be presented as discrete dosage forms, such as hardor soft capsules, cachets, troches, lozenges, or tablets, or liquids oraerosol sprays each containing a predetermined amount of an activeingredient as a powder or in granules, a solution, or a suspension in anaqueous or non-aqueous liquid, an oil-in-water emulsion, or awater-in-oil liquid emulsion, or dispersible powders or granules, orsyrups or elixirs. Such dosage forms can be prepared by any of themethods of pharmacy, which typically include the step of bringing theactive ingredient(s) into association with the carrier. In general, thecomposition are prepared by uniformly and intimately admixing the activeingredient(s) with liquid carriers or finely divided solid carriers orboth, and then, if necessary, shaping the product into the desiredpresentation. For example, a tablet can be prepared by compression ormolding, optionally with one or more accessory ingredients. Compressedtablets can be prepared by compressing in a suitable machine the activeingredient(s) in a free-flowing form such as powder or granules,optionally mixed with an excipient such as, but not limited to, abinder, a lubricant, an inert diluent, and/or a surface active ordispersing agent. Molded tablets can be made by molding in a suitablemachine a mixture of the powdered compound or salt of any one of theFormulas or sub Formulas described herein (e.g., Formula (I), Formula(X), Formula (L), ect.,) moistened with an inert liquid diluent.

In some embodiments, the disclosure provides a pharmaceuticalcomposition for injection containing a compound or salt of any one ofthe Formulas described herein (e.g., Formula (I), Formula (X), Formula(L), ect.,) and a pharmaceutical excipient suitable for injection.Components and amounts of agents in the composition are as describedherein.

In certain embodiments, the compound or salt of any one of the Formulasor sub Formulas described herein (e.g., Formula (I), Formula (X),Formula (L), ect.,) may be formulated for injection as aqueous or oilsuspensions, emulsions, with sesame oil, corn oil, cottonseed oil, orpeanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueoussolution, and similar pharmaceutical vehicles.

Aqueous solutions in saline are also conventionally used for injection.Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and thelike (and suitable mixtures thereof), cyclodextrin derivatives, andvegetable oils may also be employed. The proper fluidity can bemaintained, for example, by the use of a coating, such as lecithin, forthe maintenance of the required particle size in the case of dispersionand by the use of surfactants. The prevention of the action ofmicroorganisms can be brought about by various antibacterial andantifungal agents, for example, parabens, chlorobutanol, phenol, sorbicacid, thimerosal, and the like.

Pharmaceutical compositions may also be prepared from a compound or saltof any one of the Formulas or sub Formulas described herein (e.g.,Formula (I), Formula (X), Formula (L), ect.,) and one or morepharmaceutically acceptable excipients suitable for transdermal,inhalative, sublingual, buccal, rectal, intraosseous, intraocular,intranasal, epidural, or intraspinal administration. Preparations forsuch pharmaceutical composition are well-known in the art. See, e.g.,Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds.,Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Prattand Taylor, eds., Principles of Drug Action, Third Edition, ChurchillLivingston, New York, 1990; Katzung, ed., Basic and ClinicalPharmacology, Ninth Edition, McGraw Hill, 2003; Goodman and Gilman,eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGrawHill, 2001; Remingtons Pharmaceutical Sciences, 20th Ed., LippincottWilliams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia,Thirty-Second Edition (The Pharmaceutical Press, London, 1999).

The disclosure also provides kits. The kits may include a compound orsalt of any one of the Formulas or sub Formulas described herein (e.g.,Formula (I), Formula (X), Formula (L), ect.,) and one or more additionalagents in suitable packaging with written material that can includeinstructions for use, discussion of clinical studies, listing of sideeffects, and the like. Such kits may also include information, such asscientific literature references, package insert materials, clinicaltrial results, and/or summaries of these and the like, which indicate orestablish the activities and/or advantages of the composition, and/orwhich describe dosing, administration, side effects, drug interactions,or other information useful to the health care provider. Suchinformation may be based on the results of various studies, for example,studies using experimental animals involving in vivo models and studiesbased on human clinical trials. The kit may further contain anotheragent. In some embodiments, a compound or salt of any one of theFormulas or sub Formulas described herein (e.g., Formula (I), Formula(X), Formula (L), ect.,) and the agent are provided as separatecompositions in separate containers within the kit. In some embodiments,a compound or salt of any one of the Formulas or sub Formulas describedherein (e.g., Formula (I), Formula (X), Formula (L), ect.,) and theagent are provided as a single composition within a container in thekit. Suitable packaging and additional articles for use (e.g., measuringcup for liquid preparations, foil wrapping to minimize exposure to air,and the like) are known in the art and may be included in the kit. Kitsdescribed herein can be provided, marketed and/or promoted to healthproviders, including physicians, nurses, pharmacists, formularyofficials, and the like. Kits may also, in some embodiments, be marketeddirectly to the consumer.

Therapeutic Applications for Compounds of Groups 1, 2, and 3

In one aspect, the present disclosure provides a method of inhibitingmTORC1, comprising administering a compound or salt of any one of theFormulas or sub Formulas described herein (e.g., Formula (I), Formula(X), Formula (L), ect.,). In one aspect, the present disclosure providesa method of inhibiting mTORC1 without appreciably modulating mTORC2,comprising administering a compound or salt of any one of the Formulasdescribed herein (e.g., Formula (I), Formula (X), Formula (L), ect.,).In certain embodiments, the compounds and salts of the disclosure do notappreciably inhibit mTORC2.

While not being bound to any particular mechanism, a compound or salt ofany one of the Formulas or sub Formulas described herein (e.g., Formula(I), Formula (X), Formula (L), ect.,) may show reduced side effectsrelative to rapamycin. In particular, compounds or salts of thedisclosure may not appreciably impact the gastrointestinal and/orcardiac systems. In certain embodiments the compounds of the disclosuremay be administered in larger dosing amounts or over longer periods oftime than the prescribed dosing amounts or timeframes for rapamycin. Forexample of the intended timeframes, a compound or salt of any one of theFormulas or sub Formulas described herein (e.g., Formula (I), Formula(X), Formula (L), ect.,) may be administered daily, every other day,once a week, once every two weeks over a period of time, such as 2months or more, 4 months or more, 6 months or more, 1 year or more, oreven two years or more. For example of the intended dosing, a compoundor salt of any one of the Formulas or sub Formulas described herein(e.g., Formula (I), Formula (X), Formula (L), ect.,) may be administeredin dose, 30% or greater, 50% greater, 80% or greater than rapamycinindicated dosing for the same indication.

In certain embodiments, a compound or salt of any one of the Formulas orsub Formulas described herein (e.g., Formula (I), Formula (X), Formula(L), ect.,) is administered to a subject in need thereof for thetreatment and/or prevention of a tauopathy (including but not limited toAlzheimer's disease, Parkinson's disease, progressive supranuclear palsy(PSP), corticobasal degeneration, corticobasal syndrome, frontotemporaldementia, frontotemporal lobar degeneration (FTLD) including but notlimited to FTLD-17, behavior variant FTD, primary progressive aphasia(semantic, agrammatic or logopenic variants), argyrophilic graindisease, Pick's disease, globular glial tauopathies, primary age-relatedtauopathy (including neurofibrillary tangle dementia), chronic traumaticencephalopathy (CTE)-traumatic brain injury and aging-related tauastrogliopathy), an mTORopathy (including but not limited to tuberoussclerosis complex (TSC)), an mTORopathy associated with epilepticseizures, focal cortical dysplasia (FCD), ganglioglioma,hemimegalencephaly, neurofibromatosis 1, Sturge-Weber syndrome, Cowdensyndrome, PMSE (Polyhydramnios, Megalencephaly, Symptomatic Epilepsy)),familial multiple discoid fibromas (FMDF), an epilepsy/epilepticseizures (both genetic and acquired forms of the disease such asfamilial focal epilepsies, epileptic spasms, infantile spasms (IS),status epilepticus (SE), temporal lobe epilepsy (PLE) and absenceepilepsy), rare diseases associated with a dysfunction of mTORC1activity (e.g., lymphangioleiomyomatosis (LAM), Leigh's syndrome,Friedrich's ataxia, Diamond-Blackfan anemia, etc.), metabolic diseases(e.g., obesity, Type II diabetes, etc.), autoimmune and inflammatorydiseases (e.g., Systemic Lupus Erythematosus (SLE), multiple sclerosis(MS) psoriasis, etc.), cancer, a fungal infection, a proliferativedisease, the maintenance of immunosuppression, transplant rejection,traumatic brain injury, autism, lysosomal storage diseases andneurodegenerative diseases associated with an mTORC1 hyperactivity(e.g., Parkinson's, Huntington's disease, etc.), aberrant compoundaccumulation, dysfuntion of the autophagy mechanisms, and generallyincluding but not limited to disorders that can be modulated byselective inhibition of the mTORC1 pathway.

In certain embodiments, a compound or salt of any one of the Formulas orsub Formulas described herein (e.g., Formula (I), Formula (X), Formula(L), ect.,) is administered to a subject in need thereof for treatmentand/or prevention of a tauopathy selected from the group consisting of:progressive supranuclear palsy, dementia pugilistica (chronic traumaticencephalopathy), frontotemporal dementia, lytico-bodig disease(parkinson-dementia complex of guam), tangle-predominant dementia (withnfts similar to Alzheimer's disease, but without plaques), gangliogliomaand gangliocytoma, meningioangiomatosis, subacute sclerosingpanencephalitis, lead encephalopathy, tuberous sclerosis, Pick'sdisease, corticobasal degeneration(tau proteins are deposited in theform of inclusion bodies within swollen or “ballooned” neurons),Alzheimer's disease, Parkinson's disease, Huntington's disease,frontotemporal dementia, and frontotemporal lobar degeneration.

In certain embodiments, a compound or salt of any one of the Formulas orsub Formulas described herein (e.g., Formula (I), Formula (X), Formula(L), ect.,) is administered to a subject in need thereof for thetreatment and/or prevention of a tauopathy selected from the groupconsisting of: Alzheimer's disease, Parkinson's disease, progressivesupranuclear palsy (PSP), corticobasal degeneration, corticobasalsyndrome, frontotemporal dementia, frontotemporal lobar degeneration(FTLD) including but not limited to FTLD-17, behavior variant FTD,primary progressive aphasia (semantic, agrammatic or logopenicvariants), argyrophilic grain disease, Pick's disease, globular glialtauopathies, primary age-related tauopathy (including neurofibrillarytangle dementia), chronic traumatic encephalopathy (CTE)-traumatic braininjury and aging-related tau astrogliopathy.

In certain embodiments, a compound or salt of any one of the Formulas orsub Formulas described herein (e.g., Formula (I), Formula (X), Formula(L), ect.,) is administered to a subject in need thereof for thetreatment and/or prevention of a mTORopathy. The mTORopathy may be, forexample, Tuberous Sclerosis, Focal Cortical Dysplasia, or a PTEN(Phosphatase and tensin homolog) disease, etc. The mTORopathy may be adisease or disorder described elsewhere herein.

In certain embodiments, a compound or salt of any one of the Formulas orsub Formulas described herein (e.g., Formula (I), Formula (X), Formula(L), ect.,) is administered to a subject in need thereof for thetreatment and/or prevention of cancer. Non-limiting examples of cancerscan include Acute lymphoblastic leukemia (ALL); Acute myeloid leukemia;Adrenocortical carcinoma; Astrocytoma, childhood cerebellar or cerebral;Basal-cell carcinoma; Bladder cancer; Bone tumor, osteosarcoma/malignantfibrous histiocytoma; Brain cancer; Brain tumors, such as, cerebellarastrocytoma, malignant glioma, ependymoma, medulloblastoma, visualpathway and hypothalamic glioma; Brainstem glioma; Breast cancer;Bronchial adenomas/carcinoids; Burkitt's lymphoma; Cerebellarastrocytoma; Cervical cancer; Cholangiocarcinoma; Chondrosarcoma;Chronic lymphocytic leukemia; Chronic myelogenous leukemia; Chronicmyeloproliferative disorders; Colon cancer; Cutaneous T-cell lymphoma;Endometrial cancer; Ependymoma; Esophageal cancer; Eye cancers, such as,intraocular melanoma and retinoblastoma; Gallbladder cancer; Glioma;Hairy cell leukemia; Head and neck cancer; Heart cancer; Hepatocellular(liver) cancer; Hodgkin lymphoma; Hypopharyngeal cancer; Islet cellcarcinoma (endocrine pancreas); Kaposi sarcoma; Kidney cancer (renalcell cancer); Laryngeal cancer; Leukemia, such as, acute lymphoblastic,acute myeloid, chronic lymphocytic, chronic myelogenous and, hairy cell;Lip and oral cavity cancer; Liposarcoma; Lung cancer, such as, non-smallcell and small cell; Lymphoma, such as, AIDS-related, Burkitt; Lymphoma,cutaneous T-Cell, Hodgkin and Non-Hodgkin, Macroglobulinemia, Malignantfibrous histiocytoma of bone/osteosarcoma; Melanoma; Merkel cell cancer;Mesothelioma; Multiple myeloma/plasma cell neoplasm; Mycosis fungoides;Myelodysplastic syndromes; Myelodysplastic/myeloproliferative diseases;Myeloproliferative disorders, chronic; Nasal cavity and paranasal sinuscancer; Nasopharyngeal carcinoma; Neuroblastoma; Oligodendroglioma;Oropharyngeal cancer; Osteosarcoma/malignant fibrous histiocytoma ofbone; Ovarian cancer; Pancreatic cancer; Parathyroid cancer; Pharyngealcancer; Pheochromocytoma; Pituitary adenoma; Plasma cell neoplasia;Pleuropulmonary blastoma; Prostate cancer; Rectal cancer; Renal cellcarcinoma (kidney cancer); Renal pelvis and ureter, transitional cellcancer; Rhabdomyosarcoma; Salivary gland cancer; Sarcoma, Ewing familyof tumors; Sarcoma, Kaposi; Sarcoma, soft tissue; Sarcoma, uterine;Sezary syndrome; Skin cancer (non-melanoma); Skin carcinoma; Smallintestine cancer; Soft tissue sarcoma; Squamous cell carcinoma; Squamousneck cancer with occult primary, metastatic; Stomach cancer; Testicularcancer; Throat cancer; Thymoma and thymic carcinoma; Thymoma; Thyroidcancer; Thyroid cancer, childhood; Uterine cancer; Vaginal cancer;Waldenstrom macroglobulinemia; Wilms tumor and any combination thereof.

In certain embodiments, a compound or salt of any one of the Formulas orsub Formulas described herein (e.g., Formula (I) of the first aspect,Formula (X) of the second aspect, Formula (L) of the third aspect,ect.,) is administered to a subject in need thereof for the treatmentand/or prevention of seizures and/or seizure related disorders. Theseizure related disorders may include but not limited to: West syndrome,Focal Cortical Dysplasia (FCD), tuberous sclerosis complex (TSC),childhood absence epilepsy, benign focal epilepsies of childhood,juvenile myoclonic epilepsy (JME), temporal lobe epilepsy, frontal lobeepilepsy, refractory epilepsy, Lennox-Gastaut syndrome, occipital lobeepilepsy, 5 Proteus syndrome, hemi-megalencephaly syndrome (HMEG),megalencephaly syndrome (MEG), megalencephaly-capillary malformation(MCAP), megalencephalypolymicrogyria-polydactyly-hydrocephalus syndrome(MPPH) and PTEN disorders.

A compound according any therapeutic compound disclosed herein for usein the treatment and/or prevention of disorders that include theprocesses of fibrosis and/or inflammation (e.g., liver and kidneydisorders). The disorders may include but not limited to liver fibrosis(which may occur in end-stage liver disease); liver cirrhosis; liverfailure due to toxicity; non-alcohol-associated hepatic steatosis orNASH; and alcohol-associated steatosis. Another example may be kidneyfibrosis, which may occur as a result of acute kidney injury, chronickidney disease, or diabetic nephropathy can induce kidney fibrosis andinflammation. The disorder may include polycystic kidney disease,ischemia/reperfusion injury, transplantation, adriamycin nephropathy,unilateral ureteral obstruction (UUO), glomerulopathy, IgA nephropathy,focal segmental glomerulosclerosis (FSGS), Lupus mesangial proliferativenephritis.

A compound according any therapeutic compound disclosed herein for usein the treatment and/or prevention of acute or chronic organ or tissuetransplant rejection, for example, heart, lung, combined heart-lung,liver, kidney, pancreatic, skin or corneal transplants, prevention ofgraft-versus-host disease, such as following bone marrowtransplantation, etc.

A compound according any therapeutic compound disclosed herein for usein the treatment and/or prevention of autoimmune diseases and/or andinflammatory conditions include in particular inflammatory conditionswith an etiology that may include an autoimmune component such asarthritis (for example rheumatoid arthritis, arthritis chronicaprogrediente and arthritis deformans) and rheumatic diseases. Examplesmay include autoimmune hematological disorders (including e.g. hemolyticanemia, aplastic anemia, pure red cell anaemia and idiopathicthrombocytopenia), systemic lupus erythematosus, polychondritis,scleroderma, Wegener granulamatosis, dermatomyositis, chronic activehepatitis, myasthenia gravis, psoriasis, Steven-Johnson syndrome,idiopathic sprue, autoimmune inflammatory bowel disease (including e. g.ulcerative colitis and Crohn's disease) endocrine ophthalmopathy, Gravesdisease, sarcoidosis, multiple sclerosis, primary biliary cirrhosis,juvenile diabetes (diabetes mellitus type I), uveitis (anterior andposterior), keratoconjunctivitis sicca and vernal keratoconjunctivitis,interstitial lung fibrosis, psoriatic arthritis, glomerulonephritis(with and without nephrotic syndrome, e.g. including idiopathicnephrotic syndrome or minimal change nephropathy) and juveniledermatomyositis.

A compound according any therapeutic compound disclosed herein for usein the treatment and/or prevention of mitochondrial diseases ordisorders.

A compound according any therapeutic compound disclosed herein for usein the treatment and/or prevention of smooth muscle cell proliferationmigration leading to vessel intimal thickening, blood vesselobstruction, obstructive coronary atherosclerosis, or restenosis.

In certain embodiments, the disclosure provides a method of treatingdisease characterized by hyperactivation of mTORC1. The followingreferences include methods for evaluating mTORC (e.g., mTORC1) activity:T. O'Reilly et al., Translational Oncology, v3, i2, p 65-79, (2010); J.Peralba, Clinical Cancer Research, v9 , i8, p 2887-2892 (2003); D. R.Moore et al., Acta Physiologica, v201, i3, p 365-372 (2010); M.Dieterlen., Clinical Cytometry, v82B, i3, p151-157, (2012); the contentsof each of which are incorpoarated by reference herein.

In certain embodiments, the disclosure provides a method of treatingage-related diseases. It may be established that modulation of mTORC1signaling may prolong lifespan and may delay the onset of age-relateddiseases across a wide array of organisms, ranging from flies tomammals, thus possibly providing therapeutic options for preventing ortreating age-related diseases in humans. In a recent clinical studyMannick et al. (mTOR inhibition improves immune function in the elderly,Sci Transl Med. 2014 Dec. 24; 6(268):268ra179. doi:10.1126/scitranslmed.3009892) may have showed that mTOR inhibitionimproves the immune function in the elderly.

In certain embodiments, the disclosure provides a method of treatingmitochondrial diseases. Mitochondrial myopathy and mitochondrial stressmay be mitochondrial disorders as described in Chinnery, P. F. (2015);EMBO Mol. Med. 7, 1503-1512; Koopman, W. J. et al., 10 (2016); EMBO Mol.Med. 8, 311-327and Young, M. J., and Yound and Copeland, W. C. (2016);Curr. Opin. Genet. Dev. 38, 52-62.

In certain embodiments, the disclosure provides a method of treatingdiseases of impaired autophagy. In some cases they may include impairedautophagies that result in mitochondrial damage, lysosomal storagediseases, cancer, Crohn's disease, etc. In some cases the impairedautophagies may be as described in Jiang P. & Mizushima, N., Autophagyand human diseases, Cell Research volume 24, p.69-79 (2014).

In certain embodiments, a compound or salt of the disclosure is used toinduce heterodimerization of FKBP12 and the FRB domain of mTOR. ChemicalInduction of Dimerization (CID) can be employed as a biological tool tospatially manipulate specific molecules, e.g., peptides andpolypeptides, within cells at precise times to control a particularactivity. Uses of CID include experimental investigations to elucidatecellular systems and therapeutic uses to regulate cell-based therapies.Exemplary uses include activation of cells used to promote engraftment,to treat diseases or conditions, or to control or modulate the activityof therapeutic cells that express chimeric antigen receptors orrecombinant T cell receptors. Compounds of the disclosure maybe used inthe development of inducible systems or molecular switches to controlcell signaling.

In certain embodiments, a compound or salt of any one of the Formulas orsub Formulas described herein (e.g., Formula (I), Formula (X), Formula(L), ect.,) is administered to a subject in need thereof for thetreatment and/or prevention of diabetic nephropathy, kidney-relatedcomplications of type 1 diabetes and type 2 diabetes, autosomal dominantpolycystic kidney disease (ADPKD), autosomal recessive polycystic kidneydisease (ARPKD), kidney diseases associated with cyst formation orcystogenesis, focal segmental glomerulosclerosis (FSGS) and otherdiseases associated with sclerosis of the kidney (glomerulopathy, IgAnephropathy, Lupus mesangial proliferative nephritis), laminopathies,age-related macular degeneration (AMD), diabetic macular edema, diabeticretinopathy, glaucoma, age related retinal disease, immune systemsenescence, respiratory tract infections, urinary tract infections,heart failure, osteoarthritis, pulmonary arterial hypertension (PAH),and/or chronic obstructive pulmonary disease (COPD).

In certain embodiments, a compound or salt of any one of the Formulas orsub Formulas described herein (e.g., Formula (I), Formula (X), Formula(L), ect.,) is administered to a subject in need thereof for thetreatment and/or prevention of Lymphangioleiomyomatosis (LAM) and/orpolycystic kidney disease.

The use of rapamycin as a dimerizing agent is limited by side effectsassociated with mTOR inhibition. mTOR inhibition can lead to reductionsin cell growth and proliferation as well as possible immunosuppression.In contrast, compounds of the present disclosure may present anadvantage over rapamycin due to the high selectivity for mTOR1 overmTOR2. mTOR2 inhibition is associated with the negative side effectsaffiliated with rapamycin. As the presently described compounds areselective from mTOR1 and have minimal impact on mTOR2.

The tom “multimerize” or multimerization refers to the dimerization oftwo peptides or polypeptides, or the multimerization of more than twopeptides or polypeptides, for example, the dimerization of FKBP12 andthe FRB domain of mTOR.

Inducible FKBP12/FRB-based multimerization systems can also beincorporated into chimeric antigen receptor (CAR) T cells which can beused, for example, in immunotherapy applications. One type ofimmunotherapy is adoptive cell transfer in which a subject's immunecells are collected and modified ex vivo, e.g., CAR-modified T cells, toprovide for specific and targeted tumor cell killing when the modifiedcells are returned to the body. T Cells from a patient's blood may beextracted and genetically engineered to express CARs on the cellsurface. The components of a CAR typically include an extracellular,antibody-derived single chain variable fragment (scFv), whichspecifically recognizes a target tumor cell antigen, and one or moremulticellular T-cell-derived signaling sequences fused to the scFv.Binding of the scFv region to an antigen results in activation of the Tcell through the signaling domains of the CAR. In certain embodiments, acompound of the disclosure may be administered to a cell to activate aCAR-T cell with an FKBP12/FRB-based multimerization system. In certainembodiments, the disclosure provides a method of activating the growthof a cell, e.g., CAR-T cell, containing an FKBP protein fusion and anFRB fusion protein by contacting the cell with a compound or salt of anyone of the Formulas described herein (e.g., Formula (I), Formula (X),Formula (L), ect.,).

In some instances, it is beneficial to increase the activity of atherapeutic cell. For example, co-stimulating polypeptides may be usedto enhance the activation of T Cells, and of CAR-expressing T cellsagainst antigens, which would increase the potency of the adoptiveimmunotherapy. These treatments are used, for example, to treat tumorsfor elimination, and to treat cancer and blood disorders, but thesetherapies may have negative side effects. Overzealous on-target effects,such as those directed at large tumor masses, can lead to cytokinestorms associated with tumor lysis syndrome (TLS), cytokine releasesyndrome (CRS) or macrophage activation syndrome (MAS). In someinstances of therapeutic cell-induced adverse events, there is a needfor rapid and near complete elimination of the therapeutic cells. Ifthere is a need to reduce the number of transferred CAR-T cells, aninducing ligand may be administered to the subject being treated,thereby inducing apoptosis specifically of the modified T cells. Forexample, multimeric versions of the ligand binding domains FRB and/orFKBP12 or variants thereof, such as those described in WO 2020/076738,fused to caspase proteins and expressed in a modified therapeutic cellcan serve as scaffolds that permit the spontaneous dimerization andactivation of the caspase units upon recruitment through the FRB and/orFKBP12 with a chemical inducing agent such as a compound or salt of anyone of the Formulas described herein (e.g., Formula (I), Formula (X),Formula (L), ect.,). In certain embodiments, the disclosure provides amethod of inhibiting the growth of a cell containing an FKBP proteinfusion and an FRB fusion protein by contacting the cell with a compounda compound or salt of any one of the Formulas described herein (e.g.,Formula (I), Formula (X), Formula (L), ect.,).

EXAMPLES

The following examples are offered to illustrate, but not to limit theclaimed invention. It will be recognized that these preparation methodsare illustrative and not limiting. Using the teaching provided herein,numerous other methods of producing the rapamycin analogs describedherein will be available to one of skill in the art.

Where designated the absolute stereochemistry is assigned by analogybased upon on the analytical data for rapamycin (e.g., at C16 and C28for the compounds described elsewhere herein).

Example 1 NMR Spectroscopy

¹H NMR spectra were recorded at 400 MHz on a Bruker Avance III NMRspectrometer. Samples were prepared in deuterated chloroform (CDCl₃) ordimethylsulfoxide (DMSO-d₆) and the raw data were processed using theMNova NMR software.

Example 2 UPLC-MS Analysis

LCMS analysis was conducted on a Waters Acquity UPLC system consist ofan Acquity i-Class Sample Manager-FL, Acquity i-Class Binary SolventManager and Acquity Class UPLC Column Manager. UV detection was achievedusing an Acquity i-Class UPLC PDA detector (scanning from 210-400 nm),whereas mass detection was achieved using an Acquity QDa detector (massscanning from 100-1250 Da; positive and negative modes simultaneously).A Waters Acquity UPLC CSH C18 Column (2.1×100 mm); particle size 1.7 μmwas used to achieve the separation of the analytes.

Samples were prepared by dissolving (with or without sonication) into 1mL of MeOH or MeCN. The resulting solutions were filtered through a 0.2μm syringe filter before being submitted for analysis. All of thesolvents (including formic acid) used were used as the HPLC grade.

Details of the analytical method used for this work are presented below.

Method 1: 0.1% v/v Formic acid in water [Eluent A]; 0.1% v/v Formic acidin MeCN [Eluent B]; Flow rate 0.8 mL/min; injection volume 2 μL and 1.5min equilibration time between samples.

TABLE 1 UPLC-MS parameters Time (min) Eluent A (%) Eluent B (%) 0.00 5050 10 0 100 10.10 50 50 12 5 95

Example 3 Prep HPLC

Method 1: Compounds were purified via reverse phase columnchromatography on a Gemini NX C18 (30 mm×150 mm, 5 μm) cartridge elutingwith a H₂O (0.2% formic acid):MeCN gradient. Gradients were selectedbased on analytical separation.

Example 4 SFC

SFC was carried out using the following method:

Method 1: Greensep 2EP (19 mm×100 mm, 5 μm); CO₂/MeCN. Gradients wereselected based on analytical separation.

Synthesis of Intermediates Example 5 Synthesis of2-[2-(2-methoxyethoxy)ethoxy]ethane-1-sulfonyl chloride

A stirred mixture of 1-bromo-2-[2-(2-methoxyethoxy)ethoxy]ethane (2.50g, 11.0 mmol) and sodium sulfite [Na₂SO₃] (1.39 g, 11.0 mmol) in H₂O(13.4 mL) was heated at reflux for 18 h. The mixture was concentratedunder reduced pressure, then taken up in ethanol (20 mL) andconcentrated to dryness. A 1:1 mixture of TBME/hexanes (20 mL) wasadded, and again the mixture was concentrated to dryness. This finalstep was repeated to give sodium2-[2-(2-methoxyethoxy)ethoxy]ethane-1-sulfonate as a solid (as a mixturewith sodium bromide) which was used without analysis or purification.POCl₃ (6.8 mL, 74.1 mmol) was added, and the mixture heated at 70° C.for 4 h, then stirred at rt overnight. The mixture was added carefullyto ice-H₂O (50 mL), then the product extracted with EtOAc (3×50 mL). Thecombined organic extracts were dried (Na₂SO₄) and concentrated underreduced pressure to give 2-[2-(2-methoxyethoxy)ethoxy]ethane-1-sulfonylchloride) (1.90 g, 70%) as an oil.

¹H NMR (400 MHz, CDCl₃) δ 4.14-4.04 (m, 2H), 3.99 (t, J=6.0 Hz, 2H),3.78-3.69 (m, 2H), 3.69-3.61 (m, 4H), 3.55 (dd, J=5.7, 3.4 Hz, 2H), 3.38(s, 3H).

Example 6 Synthesis ofN-tert-butyl-2-[2-(2-methoxyethoxy)ethoxy]ethane-1-sulfonamide

To a solution of tent-butylamine (0.70 mL, 4.43 mmol) in THF (4.4 mL) at−20° C. was added 2-[2-(2-methoxyethoxy)ethoxy]ethane-1-sulfonylchloride (0.84 g, 2.21 mmol) dropwise. The mixture was allowed to warmtort, and stirred overnight. The resulting precipitate was filtered, thefilter cake was washed with THF (10 mL), and the combined filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (20-100% EtOAc in hexanes; staining withacidic vanillin solution) to giveN-tert-butyl-2-[2-(2-methoxyethoxy)ethoxy]ethane-1-sulfonamide (0.144 g,23%) as an oil. ¹H NMR (400 MHz, CDCl₃) δ 4.77 (s, 1H), 3.90 (t, J=5.8Hz, 2H), 3.64 (d, J=11.5 Hz, 6H), 3.59-3.54 (m, 2H), 3.38 (s, 3H), 3.30(t, J=5.8 Hz, 2H), 1.37 (s, 9H).

Example 7 Synthesis of 2-[2-(2-methoxyethoxy)ethoxy]ethane-1-sulfonamide

To N-tert-butyl-2-[2-(2-methoxyethoxy)ethoxy]ethane-1-sulfonamide (144mg, 0.51 mmol) in DCM (2 mL) was added TFA (0.39 mL, 5.1 mmol) and themixture stirred at rt for 18 h. The mixture was concentrated underreduced pressure, followed by azeotroping with toluene (2×10 mL) and DCM(10 mL) to give 2-[2-(2-methoxyethoxy)ethoxy]ethane-1-sulfonamide as anoil which still contained some TFA, but was used without furtherpurification.

¹H NMR (400 MHz, CDCl₃) δ 4.06-3.95 (m, 2H), 3.75-3.58 (m, 9H), 3.43 (s,3H), 3.40-3.34 (m, 2H).

Example 8 Synthesis of 3-methanesulfonylpropyl trifluoromethanesulfonate

3-methanesulfonylpropan-1-ol (2.00 g, 14.5 mmol) and2,6-dimethylpyridine (1.80 mL, 15.2 mmol) were dissolved in anhydrousDCM (25 mL) and cooled to −30° C. Trifluoromethanesulfonyltrifluoromethanesulfonate (2.3 mL, 13.9 mmol) was added dropwise and themixture allowed to warm to −10° C. over 50 min. The mixture was quenchedwith H₂O (25 mL), and the layers separated. The organic layer was washedwith H₂O (25 mL) and brine (25 mL), and the organic layer was dried(Na₂SO₄), filtered, and concentrated under reduced pressure to give3-methanesulfonylpropyl trifluoromethanesulfonate (3.05 g, 78%) as anoil. ¹H NMR (400 MHz, DMSO-d₆) δ 4.36 (t, J=6.0 Hz, 2H), 3.25-3.15 (m,2H), 3.02 (s, 3H), 2.22-2.06 (m, 2H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −77.7(s).

Example 9 Synthesis of 3-[(tert-butyldimethylsilyl)oxy]propyltrifluoromethanesulfonate

To a solution of 3-[(tert-butyldimethylsilyl)oxy]propan-1-ol (5.21 g,27.4 mmol) and DIPEA (6.0 mL, 34.2 mmol) in pentane (26 mL) at 0° C. wasadded triflic anhydride (5.1 mL, 30.5 mmol), and the reaction mixturestirred at this temperature for 2 h, then filtered through a plug ofCelite. The residue was dissolved in hexane (20 mL), filtered through aplug of Celite, then concentrated under reduced pressure to give3-[(tert-butyldimethylsilyl)oxy]propyl trifluoromethanesulfonate (7.56g, 86%) as an oil.

Example 10 Synthesis of Intermediate A

To a solution of rapamycin (4.00 g, 4.4 mmol) in EtOAc (120 mL) wasadded 1H-imidazole (1.30 g, 19.0 mmol), then the reaction mixture wascooled to 0° C. TMSC1 (2.2 mL, 17.5 mmol) was added over 10 min, thenthe reaction stirred for 50 min. 0.5M H₂SO₄ (8.0 mL, 4.0 mmol) was addeddropwise over 10 min, then the mixture stirred for 20 min. The mixturewas washed sequentially with brine (120 mL), saturated sodiumbicarbonate solution (120 mL), H₂O (120 mL) and brine (120 mL). Theorganic layer was dried (Na₂SO₄), filtered, and concentrated underreduced pressure, and the resultant solid was purified by silica gelcolumn chromatography (30-60% EtOAc in heptane) to give Intermediate A(3.74 g, 87%) as a solid.

¹H NMR (400 MHz, DMSO-d₆) δ 6.52-6.32 (m, 2H), 6.31-6.07 (m, 3H), 5.48(dd, J=12.6, 10.1 Hz, 1H), 5.21-4.86 (m, 3H), 4.67-4.56 (m, 1H),4.17-3.95 (m, 3H), 3.70-3.60 (m, 1H), 3.54-3.41 (m, 1H), 3.36-3.33 (m,3H), 3.31-3.26 (m, 1H), 3.24-3.14 (m, 4H), 3.13-2.98 (m, 4H), 2.87-2.78(m, 1H), 2.76-2.66 (m, 1H), 2.49-2.42 (m, 1H), 2.41-2.30 (m, 1H),2.29-2.18 (m, 1H), 2.17-2.08 (m, 1H), 2.07-2.02 (m, 1H), 1.97-1.73 (m,6H), 1.72-1.47 (m, 11H), 1.46-1.22 (m, 6H), 1.16-0.94 (m, 7H), 0.93-0.69(m, 13H), 0.64-0.54 (m, 1H), 0.00 (s, 9H). UPLC-MS (Method 1): rt 6.47min, m/z (ES+) 1003.8 [M+NH₄]⁺

Example 11 Synthesis of Intermediate B

To a solution of Intermediate A (2.00 g, 2.0 mmol) and DIPEA (3.4 mL,19.0 mmol) in anhydrous DCM (25 mL) was added a solution of3-methanesulfonylpropyl trifluoromethanesulfonate (4.93 g, 18.3 mmol) inanhydrous DCM (7.2 mL) and the mixture was stirred for 18 h. Amberlystbasic resin (15 g) was added and stirring continued for 10 min, then themixture filtered and the resin washed with DCM (50 mL). The combinedorganic layers were washed with H₂O (2×50 mL) and brine (50 mL), thendried (Na₂SO₄), filtered, and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (40-80% EtOAcin heptane) to give Intermediate B (1.15 g, 51%) as a solid. ¹H NMR (400MHz, DMSO-d₆) δ 6.52-6.33 (m, 2H), 6.29-6.08 (m, 3H), 5.48 (dd, J=12.6,10.1 Hz, 1H), 5.19-4.90 (m, 3H), 4.16-3.96 (m, 3H), 3.69-3.53 (m, 3H),3.52-3.44 (m, 1H), 3.34-3.30 (s, 4H) 3.22-2.93 (m, 14H), 2.77-2.65 (m,1H), 2.49-2.42 (m, 1H), 2.41-2.30 (m, 1H), 2.29-2.18 (m, 1H), 2.17-2.09(m, 1H), 2.08-2.02 (m, 1H), 2.00-1.74 (m, 8H), 1.73-1.47 (m, 11H),1.46-1.22 (m, 6H), 1.16-0.95 (m, 7H), 0.94-0.71 (m, 13H), 0.69-0.57 (m,1H), 0.00 (s, 9H). UPLC-MS (Method 1): rt 6.56 min, m/z (ES+) 1123.8[M+NH₄]⁺

Example 12 Synthesis of Intermediate C

To a solution of Intermediate B (1.12 g, 1.00 mmol) in acetone (47 mL)at 0° C. was added 0.5M sulfuric acid (1.8 mL, 0.90 mmol) and themixture stirred for 2 h. The mixture was diluted with EtOAc (120 mL) andwashed sequentially with saturated aqueous sodium bicarbonate solution(2×80 mL), H₂O (2×80 mL) and brine (80 mL). The organic layer was dried(Na₂SO₄) then concentrated under reduced pressure and the residuepurified by silica gel column chromatography (20-100% EtOAc in hexanes)to give Intermediate C [also known as Compound 59] (0.91 g, 88%) as asolid. ¹H NMR (400 MHz, DMSO-d₆) δ 6.52-6.34 (m, 2H), 6.29-6.06 (m, 3H),5.47 (dd, J=12.6, 9.6 Hz, 1H), 5.30-5.24 (m, 1H), 5.18-4.89 (m, 3H),4.06-3.92 (m, 3H), 3.66-3.51 (m, 3H), 3.49-3.38 (m, 1H), 3.35-3.32 (m,4H), 3.30-3.24 (m, 1H), 3.18-3.09 (m, 5H), 3.07-2.90 (m, 8H), 2.76-2.67(m, 1H), 2.47-2.30 (m, 2H), 2.28-2.15 (m, 1H), 2.14-2.01 (m, 2H),1.96-1.77 (m, 6H), 1.76-1.47 (m, 11H), 1.46-1.20 (m, 7H), 1.15-0.93 (m,8H), 0.91-0.71 (m, 13H), 0.69-0.60 (m, 1H). UPLC-MS (Method 1): rt 4.02min, m/z (ES+) 1051.7 [M+NH₄]⁺

Example 13 Synthesis of Intermediate D

To a solution of Intermediate A (2.65 g, 2.69 mmol) in chlorobenzene (14mL) was added DIPEA (2.1 mL, 11.8 mmol). The mixture was heated to 60°C., then a solution of 3-[(tert-butyldimethylsilyl)oxy]propyltrifluoromethanesulfonate) (1.73 g, 5.4 mmol) in chlorobenzene (1 mL)was added over 1 h. The mixture was maintained at 60° C. for 1 h thenfurther 3-[(tert-butyldimethylsilyl)oxy]propyltrifluoromethanesulfonate) (1.73 g, 5.4 mmol) in chlorobenzene (1 mL)was added dropwise over 1 h. The mixture was stirred at 60° C. for 1 hthen allowed to cool and stirred at rt for 18 h. Saturated aqueoussodium bicarbonate solution (5 mL) was added and the mixture wasextracted with EtOAc (3×15 mL). The combined organic layers were eachwashed with brine (15 mL), then combined, dried (Na₂SO₄), concentratedunder reduced pressure, and the residue was purified by silica gelcolumn chromatography (EtOAc in hexanes, 10-100%) to yield IntermediateD (2.35 g, 72%) as a gum. ¹1-INMR (400 MHz, DMSO-d₆) δ 6.50-6.32 (m,2H), 6.26-6.08 (m, 3H), 5.45 (dd, J=14.7, 9.5 Hz, 1H), 5.10 (d, J=10.4Hz, 1H), 5.04-4.90 (m, 2H), 4.14-3.97 (m, 3H), 3.70-3.38 (m, 7H),3.30-3.19 (m, 3H), 3.21-2.85 (m, 9H), 2.72-2.62 (m, 1H), 2.49-2.38 (m,1H), 2.38-1.47 (m, 28H), 1.44-0.55 (m, 31H), 0.02 (s, 9H), —0.02 (s,6H). UPLC-MS (Method 1): rt 9.73 min, m/z (ES+) 1176.0 [M+NH₄]⁺

Example 14 Synthesis of Intermediate E

A solution of Intermediate D (2.34 g, 1.84 mmol) in 0.2 M HCl (2.0 mL,0.40 mmol) and THF (18 mL) was stirred at rt for 7 h. Saturated aqueoussodium bicarbonate solution (5 mL) and brine (10 mL) were added and themixture was extracted with EtOAc (3×10 mL). The combined organic layerswere washed with brine (10 mL), dried (Na₂SO₄), concentrated underreduced pressure and the residue was purified by silica gel columnchromatography (EtOAc in hexanes, 60-100%, then 4% MeOH in EtOAc) togive Intermediate E (1.54 g, 82%) as a gum. ¹H NMR (400 MHz, DMSO-d₆) δ6.49-6.34 (m, 2H), 6.28-6.04 (m, 3H), 5.46 (dd, J=14.7, 9.6 Hz, 1H),5.36-5.19 (m, 1H), 5.14-5.05 (m, 1H), 5.03-4.90 (m, 2H), 4.38-4.22 (m,1H), 4.09-3.90 (m, 4H), 3.68-3.38 (m, 5H), 3.30-3.20 (m, 1H), 3.19-2.91(m, 10H), 2.80-2.64 (m, 1H), 2.47-1.77 (m, 12H), 1.77-1.45 (m, 12H),1.45-0.90 (m, 15H), 0.90-0.57 (m, 14H). UPLC (Method 1): rt 3.93 min,m/z (ES+) 989.9 [M+NH₄]⁺

Example 15 Synthesis of Intermediate F

To a mixture of Intermediate A (1.00 g, 1.0 mmol) and dirhodiumtetraacetate (19 mg, 0.04 mmol) in DCM (9.3 mL) was added ethyl2-diazoacetate (87% solution in DCM, 0.94 mL, 7.76 mmol) in threeportions over 2 h, and the mixture stirred for 18 h. The mixture waspurified directly by silica gel column chromatography (0-50% EtOAc inhexanes) to give Intermediate F (0.82 g, 0.77 mmol, 76%) as an oil. ¹HNMR (400 MHz, DMSO-d₆) δ 6.47 (d, J=1.6 Hz, 1H), 6.45-6.32 (m, 1H),6.28-6.08 (m, 3H), 5.46 (dd, J=14.6, 9.5 Hz, 1H), 5.11 (d, J=10.3 Hz,1H), 5.03-4.97 (m, 1H), 4.95 (d, J=5.3 Hz, 1H), 4.32-4.25 (m, 1H),4.25-4.19 (m, 2H), 4.19-4.07 (m, 4H), 3.64 (d, J=12.3 Hz, 1H), 3.45 (d,J=14.2 Hz, 1H), 3.28-3.08 (m, 9H), 3.08-3.04 (m, 3H), 3.02 (s, 1H),2.78-2.65 (m, 1H), 2.50-2.41 (m, 1H), 2.36 (d, J=12.7 Hz, 1H), 2.23 (s,1H), 2.18-2.09 (m, 1H), 2.09-2.01 (m, 1H), 1.99-1.95 (m, 1H), 1.91-1.80(m, 2H), 1.77 (s, 2H), 1.64 (s, 4H), 1.62-1.52 (m, 5H), 1.43-1.32 (m,3H), 1.32-1.14 (m, 10H), 1.10-0.91 (m, 6H), 0.91-0.70 (m, 13H), 0.60 (q,J=11.9 Hz, 1H), —0.01 (s, 9H). UPLC-MS (Method 1): rt 7.34 min, m/z1089.9 [M+NH₄]⁺

Example 16 Synthesis of Intermediate G

To a solution of Intermediate F (820 mg, 0.75 mmol) in acetone (35 mL)at 0° C. was added 0.5M sulfuric acid (1.3 mL, 0.67 mmol) and themixture stirred for 1.5 h. The mixture was diluted with EtOAc (150 mL)and washed sequentially with saturated aqueous sodium bicarbonatesolution (2×75 mL), H₂O (2×75 mL) and brine (75 mL). The organic layerwas dried (Na₂SO₄), then concentrated under reduced pressure and theresidue was purified by silica gel column chromatography (10-90% EtOAcin hexanes) to give Intermediate G (0.62 g, 83%) as a solid.

¹H NMR (400 MHz, DMSO-d₆) δ 6.48-6.35 (m, 2H), 6.27-6.07 (m, 3H), 5.46(dd, J=14.7, 9.6 Hz, 1H), 5.26 (dd, J=8.9, 4.6 Hz, 1H), 5.09 (d, J=10.1Hz, 1H), 4.95 (dd, J=14.5, 7.0 Hz, 2H), 4.30-4.14 (m, 3H), 4.12-3.92 (m,3H), 3.62 (d, J=11.4 Hz, 1H), 3.43 (d, J=14.1 Hz, 1H), 3.31-3.25 (m,5H), 3.18-3.06 (m, 5H), 3.06-2.98 (m, 4H), 2.83-2.68 (m, 1H), 2.40 (d,J=8.2 Hz, 1H), 2.29-2.19 (m, 1H), 2.13-2.06 (m, 1H), 1.95 (s, 1H),1.87-1.79 (m, 2H), 1.76-1.71 (m, 2H), 1.62 (s, 3H), 1.61-1.56 (m, 2H),1.56-1.50 (m, 3H), 1.45-1.30 (m, 3H), 1.29-1.19 (m, 11H), 1.08-1.03 (m,2H), 1.03-0.89 (m, 6H), 0.89-0.70 (m, 13H), 0.61 (q, J=12.1 Hz, 1H).

UPLC-MS (Method 1): rt 5.04 min, m/z 1017.9 [M+NH₄]⁺

Example 17 Synthesis of Intermediate H

To a solution of rapamycin (197 mg, 0.22 mmol) in DCM (5.5 mL) in thedark was added titanium(IV) isopropoxide and the mixture stirred for 0.5h, then poured onto a mixture of EtOAc (20 mL) and 1M HCl (15 mL). Thelayers were separated, and the aqueous layer extracted with EtOAc (20mL). The combined organic layers were washed sequentially with saturatedaqueous sodium bicarbonate solution (10 mL), water (10 mL) and brine (10mL), then dried (Na₂SO₄) and concentrated under reduced pressure. TBMEwas added and the solution reconcentrated under reduced pressure to giveIntermediate H (162 mg, 82%) as a foam. ¹H NMR (400 MHz, DMSO-d₆) δ6.50-6.33 (m, 2H), 6.34-6.07 (m, 3H), 5.45 (dd, J=14.3, 9.7 Hz, 1H),5.10-4.88 (m, 4H), 4.68-4.52 (m, 1H), 4.08-3.94 (m, 2H), 3.90-3.78 (m,1H), 3.62 (dd, J=11.3, 2.5 Hz, 1H), 3.45-2.96 (m, 12H), 2.86-2.62 (m,3H), 2.46-2.10 (m, 3H), 2.10-1.80 (m, 2H), 1.94-1.36 (m, 17H), 1.42-0.91(m, 13H), 0.90-0.70 (m, 13H), 0.64-0.47 (m, 1H). UPLC-MS (Method 1): rt3.87 min, m/z 931.6 [M+NH₄]⁺

Example 18 Synthesis of Intermediate I

To a suspension of rapamycin (1.00 g, 1.09 mmol) in 2-methoxyethanol(2.0 mL) was added para-toluenesulfonic acid monohydrate (21 mg; 0.11mmol). The reaction mixture was stirred in the dark for 20 h, thendiluted with EtOAc (20 ml). Saturated sodium bicarbonate solution thathad been adjusted to pH 7 with 30% H₂SO₄ in water (10 mL) was added, andthe mixture stirred for 10 min. The layers were separated and theaqueous layer extracted with EtOAc (3×10 mL). The combined organics werewashed with water (10 mL), passed through a plug of silica, andconcentrated under reduced pressure. The residue was taken up in DME (20mL) and concentrated under reduced pressure, then the residue wasrecrystallised from DME to give Intermediate I (0.330 g, 32%) as whitecrystals. ¹H NMR (400 MHz, DMSO-d₆) δ 6.47 (d, J=1.6 Hz, 1H), 6.45-6.34(m, 1H), 6.27-6.07 (m, 3H), 5.47 (dd, J=14.7, 9.6 Hz, 1H), 5.27 (d,J=4.5 Hz, 1H), 5.13-5.06 (m, 1H), 4.96 (dd, J=17.7, 7.3 Hz, 2H), 4.60(d, J=4.5 Hz, 1H), 4.10-3.99 (m, 2H), 3.98-3.93 (m, 1H), 3.83-3.73 (m,1H), 3.50-3.35 (m, 4H), 3.31-3.11 (m, 12H), 2.89-2.70 (m, 3H), 2.44-2.33(m, 2H), 2.30-2.16 (m, 1H), 2.16-1.99 (m, 2H), 1.95-1.81 (m, 3H),1.77-1.72 (m, 3H), 1.71-1.60 (m, 6H), 1.60-1.55 (m, 2H), 1.55-1.51 (m,2H), 1.47-1.36 (m, 2H), 1.33-1.14 (m, 5H), 1.09-0.91 (m, 6H), 0.90-0.71(m, 14H), 0.60 (q, J=12.0 Hz, 1H). UPLC-MS (Method 1): rt 4.28 min, m/z975.8 [M+NH₄]⁺.

General Method 1 (C16 Sulfonamides) Example 19 Synthesis of Compounds 8and 9

To a stirred suspension of rapamycin (600 mg; 0.66 mmol) and2-(2-methoxyethoxy)ethane-1-sulfonamide (1293 mg; 6.6 mmol) in DCM (6.6mL) was added para-toluenesulfonic acid monohydrate (12.5 mg; 0.066mmol). The reaction mixture was stirred at room temperature for 2 h.Amberlyst A21 free base (50 mg) was added, and after stirring for 5 minwas filtered and washed with DCM (10 mL). The combined filtrate andwashings were washed with water (5×10 mL), then dried (Na₂SO₄),filtered, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (EtOAc in hexanes,20-100%), then by HPLC (Method 1). Isomers were separated by SFCchromatography to give Compound 8 (18.0 mg, 2.6%) and Compound 9 (16.0mg, 2.3%) as flocculent solids.

General Method 2 (C16 Sulfonamides) Example 20 Synthesis of Compound 25

To a solution of rapamycin (220 mg, 0.24 mmol) and2-methoxyethane-1-sulfonamide (109 mg, 0.48 mmol) in DCM (4.4 mL) at rtwas added a 0.1M solution of FeCl₃ in Et₂O (0.24 mL, 0.024 mmol) and themixture stirred for 1 h. Amberlyst A21 free base (20 mg) was added, andafter stirring for 5 min was filtered and washed with DCM (10 mL). Thecombined DCM fractions were washed with water (3×20 mL), then dried(Na₂SO₄) and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (20-100% EtOAc in hexanes),then by HPLC (Method 1) to give Compound 25 (5.5 mg, 2.1%) as aflocculent solid.

TABLE 2 Compounds of Formula J with corresponding R¹ and R²substituents. Compounds of Table 2 were synthesized using methodsdescribed herein, e.g., the procedures of Examples 5-20, and employingthe appropriate reagents. C16 stereochemical SFC t/h configurationPurification RT/ (reaction Compound R¹ R² R/S (Yes/No) mins time)  1 H

Mix^(p) N 2.28 1  2 ^(b)

S N 2.38 2  3 ^(b)

R N 2.40 2  4

Mix^(p) N 2.43 1  5 H

R Y 2.10 2  6 H

S Y 2.10 2  7 ^(a)

Mix^(p) N 2.24 1  8 H

R Y 2.18 2  9 H

S Y 2.17 2  10 ^(b,d)

R Y 2.25 2  11 ^(b,d)

S Y 2.26 2  12 ^(a,d)

S N 3.54 2 13

Mix^(p) N 2.27 1 14

Mix^(p) N 3.29 1 15

Mix^(p) N 2.41 1 16

Mix^(p) N 2.13 1 17

Mix^(p) N 2.42 2.5  18 ^(b,d)

Mix^(p) N 2.76 2 19 H

R N 4.04 0.2  20 ^(e) H

S^(g) N 4.02 0.2  21 ^(c) H

Mix^(p) N 3.19 2  22 ^(e) H

R N 3.55 0.3  23 ^(e) H

S N 3.60 0.3 24 H

Mix^(p) N 2.15 1  25 ^(f) H

S N 2.12 1

TABLE 3 Characterization of compounds of Table 2 Yield/ Compound NMR ¹HNMR (400 MHz, DMSO-d₆)^(h) % [M + NH₄]⁺  1 δ 7.69-7.26 (m, 1H),6.57-6.03 (m, 5H), 5.65- 5.1 1020.7 5.48 (m, 1H), 5.35-5.04 (m, 3H),5.03-4.92 (m, 1H), 4.64 (t, J = 6.5 Hz, 1H), 4.11-3.73 (m, 4H),3.65-3.39 (m, 2H), 3.34-3.07 (m, 9H), 2.87-2.60 (m, 3H), 2.46-1.95 (m,8H), 1.84-1.47 (m, 12H), 1.46-1.13 (m, 7H), 1.12-0.67 (m, 18H),0.66-0.53 (m, 1H). 75 out of 82 protons observed.  2 ^(b) δ 7.54 (d, J =9.3 Hz, 1H), 6.55-6.00 (m, 5H), 5.48 2.4 1140.9 (dd, J = 15.0, 9.2 Hz,1H), 5.33-5.15 (m, 1H), 5.07 (d, J = 10.1 Hz, 1H), 4.98-4.91 (m, 2H),4.38-4.14 (m, 2H), 4.11-3.79 (m, 4H), 3.76-3.39 (m, 14H), 3.29-2.89 (m,10H), 2.86-2.62 (m, 2H), 2.49-2.33 (m, 1H), 2.31-1.81 (m, 8H), 1.81-1.18(m, 22H), 1.17-0.59 (m, 20H).  3 ^(b) δ 7.37 (d, J = 8.0 Hz, 1H), 6.46(s, 1H), 6.46-6.31 1.7 1140.9 (m, 1H), 6.23-6.03 (m, 3H), 5.60 (dd, J =14.2, 8.6 Hz, 1H), 5.28-5.18 (m, 2H), 5.16-5.06 (m, 1H), 5.01-4.91 (m,1H), 4.37-4.22 (m, 2H), 4.09-3.84 (m, 3H), 3.79-3.61 (m, 4H), 3.59-3.38(m, 10H), 3.29-3.07 (m, 8H), 3.08-2.89 (m, 3H), 2.86-2.63 (m, 2H),2.48-2.36 (m, 1H), 2.35-1.81 (m, 8H), 1.81-1.16 (m, 22H), 1.19-0.88 (m,9H), 0.90-0.52 (m, 11H).  4 δ 7.54-7.34 (m, 1H), 6.71-5.99 (m, 5H),5.64- 2.6 1202.8 5.44 (m, 1H), 5.42-4.90 (m, 4H), 4.32-3.79 (m, 3H),3.76-3.38 (m, 8H), 3.37-3.22 (m, 11H), 3.21- 3.09 (m, 5H), 3.08-2.88 (m,5H), 2.87-2.63 (m, 2H), 2.47-2.28 (m, 2H), 2.27-1.80 (m, 8H), 1.79- 1.48(m, 11H), 1.47-0.72 (m, 21H), 0.71-0.60 (m, 1H). 88H out of 96 protonsobserved.  5 δ 7.42 (d, J = 8.2 Hz, 1H), 6.58-6.01 (m, 5H), 5.58 5.81078.8 (dd, J = 14.2, 8.6 Hz, 1H), 5.30-4.86 (m, 4H), 4.67- 4.51 (m,1H), 4.16-3.63 (m, 6H), 3.61-3.37 (m, 2H), 3.36-3.06 (m, 9H), 3.04-2.65(m, 6H), 2.45- 1.86 (m, 7H), 1.82-1.45 (m, 14H), 1.46-1.09 (m, 8H),1.08-0.67 (m, 14H), 0.67-0.46 (m, 1H). 79 out of 88 protons observed.  6δ 7.55 (d, J = 9.4 Hz, 1H), 6.54-5.71 (m, 5H), 5.41 4.2 1078.9 (dd, J =14.9, 9.5 Hz, 1H), 5.19 (d, J = 4.6 Hz, 1H), 5.00 (d, J = 10.1 Hz, 1H),4.88 (m, 1H), 4.67-4.51 (m, 1H), 4.27-3.64 (m, 6H), 3.47-3.31 (m, 1H),3.28-3.00 (m, 10H), 2.85-2.53 (m, 6H), 2.39-2.22 (m, 1H), 2.22-2.07 (m,1H), 2.05-1.78 (m, 5H), 1.76-1.39 (m, 12H), 1.39-1.06 (m, 7H), 1.03-0.62(m, 14H), 0.53 (q, J = 11.9 Hz, 1H). 75 out of 88 protons observed.  7^(a) δ 7.64-7.35 (m, 1H), 6.57-5.97 (m, 4H), 5.65- 10.1 1126.8 5.36 (m,1H), 5.34-4.99 (m, 2H), 4.99-4.85 (m, 1H), 4.60-4.17 (m, 1H), 4.17-3.78(m, 2H), 3.78- 3.53 (m, 3H), 3.53-3.39 (m, 9H), 3.33-3.26 (m, 7H),3.25-3.20 (m, 4H), 3.20-3.10 (m, 4H), 3.07- 2.90 (m, 3H), 2.83-2.68 (m,1H), 2.46-2.34 (m, 1H), 2.31-2.10 (m, 2H), 2.10-1.45 (m, 19H), 1.45-1.17 (m, 6H), 1.17-0.70 (m, 20H), 0.65 (q, J = 12.7 Hz, 1H).  8 δ 7.39(d, J = 8.1 Hz, 1H), 6.57-5.99 (m, 5H), 5.60 2.3 1082.8 (dd, J = 14.1,8.7 Hz, 1H), 5.33-4.89 (m, 4H), 4.72- 4.58 (m, 1H), 4.11-3.81 (m, 4H),3.79-3.62 (m, 3H), 3.56-3.38 (m, 5H), 3.32-3.22 (m, 6H), 3.21- 3.10 (m,5H), 3.07-2.95 (m, 1H), 2.91-2.64 (m, 3H), 2.45-1.84 (m, 6H), 1.83-1.13(m, 19H), 1.13- 0.69 (m, 18H), 0.66-0.47 (m, 1H). 83 of 88 protonsobserved.  9 δ 7.56 (d, J = 9.3 Hz, 1H), 6.65-5.79 (m, 5H), 5.62- 2.61082.8 4.82 (m, 5H), 4.73-4.55 (m, 1H), 4.30-3.77 (m, 4H), 3.75-3.58 (m,3H), 3.56-3.08 (m, 16H), 3.06- 2.62 (m, 4H), 2.44-2.28 (m, 1H),2.27-2.16 (m, 1H), 2.12-1.84 (m, 4H), 1.82-1.11 (m, 17H), 1.11- 0.69 (m,14H), 0.61 (q, J = 11.9 Hz, 1H). 77 out of 88 protons observed. 10^(b, d) δ 7.37-7.28 (m, 1H), 6.48-6.03 (m, 5H), 5.71- 2.2 1064.8 5.55(m, 1H), 5.32-4.90 (m, 4H), 4.49-4.39 (m, 1H), 4.10-3.89 (m, 3H),3.85-3.74 (m, 1H), 3.62- 3.40 (m, 6H), 3.31-2.92 (m, 9H), 2.84-2.65 (m,2H), 2.49-2.37 (m, 1H), 2.13-1.86 (m, 6H), 1.76- 1.23 (m, 21H),1.15-0.74 (m, 24H), 0.69-0.57 (m, 1H). 11 ^(b, d) δ 7.56 (d, J = 7.5 Hz,1H), 6.52-6.00 (m, 5H), 5.55- 1.5 1064.8 5.43 (m, 1H), 5.26 (d, J = 3.5Hz, 1H), 5.21-4.89 (m, 3H), 4.51-4.40 (m, 1H), 4.08-3.76 (m, 4H),3.67-3.39 (m, 6H), 3.36-3.33 (m, 3H), 3.31-3.22 (m, 1H), 3.18-2.93 (m,5H), 2.82-2.64 (m, 2H), 2.49-2.34 (m, 2H), 2.27-2.15 (m, 2H), 2.13-1.82(m, 6H), 1.80-1.46 (m, 12H), 1.45-0.71 (m, 30H), 0.70-0.59 (m, 1H). 12^(a, d) δ 7.53 (d, J = 9.5 Hz, 1H), 6.53-5.98 (m, 5H), 5.67- 8.0 1106.84.83 (m, 5H), 4.38-3.63 (m, 9H), 3.50-3.36 (m, 1H), 3.31-3.25 (m, 4H),3.23-2.90 (m, 6H), 2.93- 2.62 (m, 1H), 2.48-1.82 (m, 9H), 1.77-1.49 (m,13H), 1.48-1.13 (m, 8H), 1.13-0.71 (m, 25H), 0.63 (q, J = 11.9 Hz, 1H).13 δ 7.63-7.43 (m, 1H), 6.52-6.01 (m, 5H), 5.64- 16.2 1096.8 5.47 (m,1H), 5.39-5.02 (m, 3H), 4.95 (t, J = 5.9 Hz, 1H), 4.34-4.25 (m, 2H),4.10-3.68 (m, 4H), 3.68- 3.36 (m, 8H), 3.30 (s, 3H), 3.25-3.07 (m, 8H),3.06- 2.86 (m, 2H), 2.86-2.64 (m, 1H), 2.48-2.34 (m, 1H), 2.34-1.81 (m,8H), 1.81-1.48 (m, 17H), 1.47- 1.20 (m, 5H), 1.15-0.56 (m, 20H). 14 δ7.67-7.33 (m, 1H), 6.52-6.44 (m, 1H), 6.40- 12.9 1124.8 5.97 (m, 4H),5.67-5.43 (m, 1H), 5.29-5.22 (m, 1H), 5.06 (d, J = 10.2 Hz, 1H),5.00-4.87 (m, 2H), 4.24-4.17 (m, 3H), 4.12-4.03 (m, 2H), 4.03-3.89 (m,1H), 3.84 (d, J = 5.3 Hz, 1H), 3.68-3.50 (m, 3H), 3.48-3.42 (m, 1H),3.30-3.25 (m, 4H), 3.24-2.92 (m, 11H), 2.85-2.62 (m, 1H), 2.45-2.12 (m,2H), 2.10-1.80 (m, 3H), 1.79-1.46 (m, 15H), 1.45-1.12 (m, 8H), 1.10-0.74(m, 16H), 0.59 (q, J = 12.2 Hz, 1H). 83 out of 90 protons observed. 15 δ7.56-7.31 (m, 1H), 6.55-5.99 (m, 5H), 5.62-5.44 11.8 1078.9 (m, 1H),5.33-5.15 (m, 2H), 5.12-5.02 (m, 1H), 5.02-4.91 (m, 1H), 4.37-4.21 (m,1H), 4.10-3.70 (m, 4H), 3.64-3.37 (m, 6H), 3.32-3.21 (m, 4H), 3.21-3.07(m, 4H), 3.07-2.90 (m, 2H), 2.82-2.64 (m, 1H), 2.48-2.34 (m, 1H),2.34-1.81 (m, 8H), 1.81-1.17 (m, 20H), 1.17-0.57 (m, 26H). 16 δ7.71-7.46 (m, 1H), 6.60-6.49 (m, 1H), 6.42- 3.6 1082.9 6.03 (m, 4H),5.63-5.39 (m, 2H), 5.38-4.89 (m, 5H), 4.54-4.46 (m, 1H), 4.12-3.77 (m,4H), 3.76- 3.66 (m, 1H), 3.65-3.40 (m, 7H), 3.34-2.92 (m, 13H),2.82-2.65 (m, 2H), 2.47-2.31 (m, 2H), 2.30- 1.85 (m, 7H), 1.82-1.20 (m,17H), 1.18-0.71 (m, 18H), 0.68-0.59 (m, 1H). 86 out of 88 protonsobserved. 17 δ 7.70-7.41 (m, 1H), 6.57-6.48 (m, 1H), 6.47- 10.5 1158.96.05 (m, 4H), 5.64-5.01 (m, 4H), 4.95 (d, J = 5.9 Hz, 1H), 4.12-3.67 (m,4H), 3.68-3.40 (m, 7H), 3.32- 2.91 (m, 18H), 2.84-2.62 (m, 1H),2.47-2.30 (m, 2H), 2.27-2.10 (m, 1H), 2.12-1.82 (m, 7H), 1.78- 1.46 (m,12H), 1.47-1.17 (m, 4H), 1.17-0.89 (m, 11H), 0.89-0.70 (m, 13H), 0.64(q, J = 12.4 Hz, 1H). 18 ^(b, d) δ 7.60-7.37 (m, 1H), 6.60-6.04 (m, 5H),5.64- 5.7 1140.7 5.38 (m, 1H), 5.32-4.90 (m, 4H), 4.11-3.72 (m, 4H),3.66-3.39 (m, 4H), 3.33-2.91 (m, 14H), 2.84- 2.63 (m, 2H), 2.47-1.81 (m,10H), 1.78-1.48 (m, 11H), 1.47-1.19 (m, 5H), 1.18-0.69 (m, 19H), 0.68-0.54 (m, 1H). 81 out of 90 protons observed. 19 δ 7.41 (d, J = 8.2 Hz,1H), 6.52-5.98 (m, 5H), 5.62- 3.0 1076.9 4.86 (m, 5H), 4.62 (d, J = 4.4Hz, 1H), 4.19-3.47 (m, 7H), 3.31-2.60 (m, 11H), 2.41-1.84 (m, 8H),1.81-1.45 (m, 20H), 1.45-0.65 (m, 31H), 0.56 (q, J = 12.6 Hz, 1H). 20^(e) δ 7.62 (d, J = 9.4 Hz, 1H), 6.59-6.00 (m, 5H), 5.54- 20.0 1076.95.40 (m, 1H), 5.29 (dd, J = 8.9, 4.4 Hz, 1H), 5.06 (d, J = 10.2 Hz, 1H),5.01-4.90 (m, 2H), 4.68-4.60 (m, 1H), 4.12-3.76 (m, 4H), 3.73-3.42 (m,1H), 3.35-3.08 (m, 10H), 3.04-2.57 (m, 4H), 2.46-1.84 (m, 6H), 1.83-1.10(m, 17H), 1.10-0.70 (m, 21H), 0.60 (q, J = 12.1 Hz, 1H). 76 out of 90protons observed. 21 ^(c) δ 7.62-7.22 (m, 1H), 6.57-5.96 (m, 5H), 5.67-8.3 1048.9 5.01 (m, 4H), 4.98-4.93 (m, 2H), 4.71-4.64 (m, 1H), 4.11-3.62(m, 4H), 3.31-3.06 (m, 9H), 3.05- 2.60 (m, 4H), 2.48-2.15 (m, 3H),2.12-1.08 (m, 29H), 1.08-0.69 (m, 21H), 0.68-0.50 (m, 1H). 84 out of 86protons observed. 22 ^(e) δ 7.45-7.26 (m, 1H), 6.75-5.99 (m, 5H), 5.76-6.8 1063.0 5.53 (m, 1H), 5.35-4.90 (m, 4H), 4.69-4.55 (m, 1H), 4.14-3.51(m, 5H), 3.33-3.06 (m, 8H), 3.05- 2.88 (m, 2H), 2.87-2.63 (m, 3H),2.46-1.97 (m, 6H), 1.95-1.34 (m, 23H), 1.33-1.04 (m, 8H), 1.03- 0.66 (m,14H), 0.66-0.49 (m, 1H). 82 out of 88 protons observed. 23 ^(e) δ7.62-7.30 (m, 1H), 6.73-6.05 (m, 5H), 5.54- 11.1 1062.9 5.44 (m, 1H),5.41-5.17 (m, 2H), 5.16-5.00 (m, 1H), 4.98-4.89 (m, 1H), 4.69-4.55 (m,1H), 4.14- 3.65 (m, 4H), 3.52-3.39 (m, 1H), 3.34-3.08 (m, 9H), 2.99-2.66(m, 4H), 2.46-2.32 (m, 2H), 2.25- 1.81 (m, 8H), 1.80-1.35 (m, 19H),1.34-0.68 (m, 23H), 0.66-0.54 (m, 1H). 83 out of 88 protons observed. 24δ 7.73-7.44 (m, 1H), 6.60-5.96 (m, 5H), 5.64- 10.9 1038.9 5.03 (m, 4H),5.00-4.92 (m, 1H), 4.68-4.57 (m, 1H), 4.12-3.67 (m, 4H), 3.65-3.47 (m,3H), 3.45- 3.37 (m, 1H), 3.34-3.06 (m, 11H), 3.04-2.92 (m, 1H),2.91-2.63 (m, 3H), 2.46-2.28 (m, 7H), 1.81- 1.46 (m, 12H), 1.45-1.12 (m,7H), 1.10-0.70 (m, 15H), 0.66-0.52 (m, 1H). 77 out of 84 protonsobserved. 25 ^(f) δ 7.58 (d, J = 9.3 Hz, 1H), 6.61-5.97 (m, 5H), 5.57-2.1 1126.7 5.36 (m, 1H), 5.31-5.22 (m, 1H), 5.08 (d, J = 10.0 Hz, 1H),5.01-4.86 (m, 2H), 4.60 (d, J = 4.8 Hz, 1H), 4.27-3.91 (m, 2H), 3.86 (d,J = 5.6 Hz, 1H), 3.65 (q, J = 6.1 Hz, 3H), 3.55-3.38 (m, 11H), 3.33-3.10(m, 24H), 3.05-2.94 (m, 1H), 2.90-2.64 (m, 3H), 2.45- 2.30 (m, 1H),2.27-1.84 (m, 5H), 1.81-1.03 (m, 13H), 1.01-0.68 (m, 15H), 0.61 (q, J =11.9 Hz, 1H).For Table 2 and Table 3: ^(a)Addition carried out at −40° C., thenallowed to warm to RT; ^(b)Addition carried out at 0° C. then allowed towarm to RT; ^(c)MeCN solvent; ^(d)40 equivalents of sulfonamide and 5equivalents of pTSA used; ^(e)Isomers separable by normal phase columnchromatography; ^(f)Prepared following General Method 2; ^(g)6:4 C16 S:Risomeric ratio; ^(h)The NMR characterization data shown for thecompounds correspond only to the major equilibrium form observed in thedeuterated solvent conditions; ^(P)Mix refers to a mixture ofdiastereomers of an undertermined amount.

General Method 3 (C-16 Ethers) Example 21 Synthesis of Compounds 50 and51

To a stirred suspension of Intermediate G (600 mg; 0.60 mmol) andcyclopropylmethanol (1.76 g; 24.4 mmol) in DCM (24 mL) at −40° C. wasadded para-toluenesulfonic acid monohydrate (570 mg; 3.00 mmol). Thereaction mixture was allowed to warm to 0° C., and stirred at thistemperature for 0.5 h. Amberlyst A21 free base (2.7 g) was added, andafter stirring for 5 min, the mixture was filtered and washed with DCM(100 mL). The combined filtrate and washings were washed with water(5×25 mL), then dried (Na₂SO₄), filtered, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(EtOAc in hexanes, 20-100%), then by HPLC (Method 1) to give Compound 50(41.5 mg, 6.7%) and Compound 51 (14.0 mg, 2.2%) as flocculent solids.

Example 22 Synthesis of Compound 56

To a mixture of Intermediate I (0.50 g, 0.52 mmol) and dirhodiumtetraacetate (9.5 mg, 0.022 mmol) in DCM (5 mL) was added 15% solutionof ethyl diazoacetate (0.76 g, 1.00 mmol) and the reaction mixturestirred for 16 h. Further 15% solution of ethyl diazoacetate (0.76 g,1.00 mmol) was added and stirring continued for 3 h. Further 15%solution of ethyl diazoacetate (0.76 g, 1.00 mmol) was added andstirring continued for 48 h. The reaction mixture was concentrated andpurified by silica gel chromatography (0-60% EtOAc in hexanes) to giveCompound 56 as an impure oil which was used in subsequent steps withoutfurther purification. A small sample was purified by HPLC (Method 1) togive Compound 56 as a flocculent solid.

Example 23 Synthesis of Compound 57

To a stirred mixture of Compound 56 (0.32 g, 0.31 mmol),2-{2-[2-(2-hydroxyethoxy)ethoxy]ethoxy}ethan-1-ol) (3 mL) and Tween80(0.78 mL) in water (16 mL) was added esterase from porcine liverlyophilized powder, ≥15 units/mg solid (20 mg). The mixture was stirredfor 48 h at rt, then further2-{2-[2-(2-hydroxyethoxy)ethoxy]ethoxy}ethan-1-ol) (0.5 mL) was added.The mixture was stirred for 432 h at rt, then further2-{2-[2-(2-hydroxyethoxy)ethoxy]ethoxy}ethan-1-ol) (1 mL), Tween80 (0.26mL) and esterase from porcine liver lyophilized powder, ≥15 units/mgsolid (25 mg) was added. The mixture was stirred for 48 h at rt, thenpurified directly by reverse phase column chromatography (5-95% MeCN inwater, with 0.1% formic acid) followed by HPLC (Method 1) to giveCompound 57 as a solid (76 mg, 24%).

Example 24 Synthesis of Compound 58

To a mixture of Intermediate A (1.00 g, 1.01 mmol) and Cs₂CO₃ (0.69 g,2.13 mmol) in DMF (28 mL) was added 1,3-propanesultone (0.26 g, 2.13mmol), and the reaction mixture was stirred at rt for 18 h. EtOAc (250mL) was added, and the mixture washed sequentially with 0.1M HCl (250mL) and brine (250 mL), then dried (Na₂SO₄) and concentrated underreduced pressure, and the residue purified by silica gel columnchromatography (0-20% MeOH in DCM) to give Compound 58 (0.78 g, 71%) asa solid.

TABLE 4 Compounds of Formula JJ with corresponding R¹ and R²substituents. Compounds of Table 4 were synthesized using the methodsdescribed herein, e.g., procedures of Examples 21-24, and employing theappropriate reagents. C16^(&) RT/ Compound t/h^(a) R₁ R₂ R/S mins 26 1.5H

S^(d) 2.21 27 1.5 H

S^(d) 2.59 28 5 H

S^(d) 3.42 29 3 H

S^(d) 3.21 30 0.5 H

S^(d) 2.38 31 1 H

S^(d) 3.55 32 3 H

S^(d) 3.86 33 2.5 H

S^(d) 3.42 34 2.5 H

S^(d) 3.61 35 1 H

S^(d) 3.13 36 4 H

S  5.88 37 4 H

R  5.62 38 168^(b) 

S^(d) 3.59 39 4 H

S^(d) 4.69 40 5 H

S^(d) 6.27 41 0.5 H

S^(d) 4.74 42 4

S  4.89 43 4

R  4.75 44 6

S^(d) 6.02 45 9

S^(d) 5.89 46 2

S  4.33 47 2

R  4.15 48 1

S^(d) 5.60 49 5.5

S^(d) 6.81 50 3.5

S  6.00 51 3.5

R  5.61 52 1.5

S  4.62 53 1.5

R  4.32 54 2

S^(d) 4.57  55 ^(c) C28 isomer (C28 S configuration) 5 H

S^(d) 3.78  56 ^(e)

S^(d) 4.87  57 ^(e)

S^(d) 3.51  58 ^(e)

S^(d) 4.20

TABLE 5 Characterization of compounds of Table 4 Yield Compound NMR ¹HNMR (400 MHz, DMSO-d₆)^(f) (%) [M + NH₄]⁺ 26 δ 6.56-6.33 (m, 2H),6.31-6.04 (m, 3H), 5.48 (dd, 11.4 1035.9 J = 14.7, 9.6 Hz, 1H), 5.25 (d,J = 4.5 Hz, 1H), 5.08 (d, J = 10.2 Hz, 1H), 5.02-4.89 (m, 2H), 4.59 (d,J = 4.5 Hz, 1H), 4.18-3.84 (m, 5H), 3.49-3.37 (m, 1H), 3.37- 3.04 (m,12H), 2.88-2.60 (m, 3H), 2.45-1.80 (m, 8H), 1.81-1.08 (m, 23H),1.09-0.90 (m, 6H), 0.90- 0.68 (m, 13H), 0.60 (q, J = 11.9 Hz, 1H). 27 δ6.51-6.34 (m, 2H), 6.27-6.02 (m, 3H), 5.46 (dd, 38.5 1063.9 J = 14.6,9.6 Hz, 1H), 5.26 (d, J = 4.4 Hz, 1H), 5.09 (d, J = 10.2 Hz, 1H),5.04-4.92 (m, 2H), 4.63-4.54 (m, 1H), 4.09-3.88 (m, 3H), 3.83-3.65 (m,1H), 3.48- 3.38 (m, 1H), 3.30-3.07 (m, 10H), 3.06-2.93 (m, 2H),2.90-2.62 (m, 5H), 2.46-2.33 (m, 3H), 2.31-2.14 (m, 2H), 2.15-1.94 (m,2H), 1.95-1.45 (m, 20H), 1.46- 1.10 (m, 7H), 1.10-0.89 (m, 6H),0.90-0.69 (m, 13H), 0.60 (q, J = 11.6 Hz, 1H). 28 δ 6.52-6.31 (m, 2H),6.31-6.06 (m, 3H), 5.45 (dd, 4.0 1002.0 J = 14.6, 9.6 Hz, 1H), 5.31-5.18(m, 1H), 5.08 (d, J = 10.3 Hz, 1H), 5.01-4.91 (m, 2H), 4.84-4.71 (m,1H), 4.59 (d, J = 4.6 Hz, 1H), 4.55-4.44 (m, 1H), 4.41- 4.29 (m, 1H),4.11-3.89 (m, 4H), 3.79-3.64 (m, 1H), 3.49-3.36 (m, 1H), 3.31-2.98 (m,9H), 2.89-2.54 (m, 4H), 2.44-2.15 (m, 4H), 2.15-1.46 (m, 21H), 1.47-1.10 (m, 7H), 1.12-0.92 (m, 6H), 0.88-0.70 (m, 13H), 0.60 (q, J = 12.0Hz, 1H). 29 δ 6.52-6.32 (m, 2H), 6.30-6.00 (m, 3H), 5.60-5.37 3.5 987.9(m, 1H), 5.37-5.18 (m, 1H), 5.14-5.04 (m, 1H), 5.01- 4.82 (m, 2H),4.61-4.57 (m, 1H), 4.09-3.45 (m, 10H), 3.49-3.35 (m, 1H), 3.28-3.13 (m,8H), 2.91- 2.63 (m, 2H), 2.47-2.16 (m, 3H), 2.14-1.95 (m, 2H), 1.95-1.47(m, 17H), 1.46-0.92 (m, 15H), 0.91-0.69 (m, 13H), 0.67-0.53 (m, 1H). 30δ 6.67-6.34 (m, 2H), 6.32-5.89 (m, 3H), 5.70-5.42 8.0 1049.9 (m, 1H),5.38-4.85 (m, 4H), 4.65-4.50 (m, 1H), 4.14- 3.65 (m, 4H), 3.58-3.40 (m,1H), 3.32-3.06 (m, 12H), 2.95-2.55 (m, 5H), 2.47-1.95 (m, 5H), 1.94-1.47 (m, 15H), 1.45-0.66 (m, 22H), 0.65-0.54 (m, 1H). 76H out of 85Hobserved. 31 δ 6.64-6.31 (m, 2H), 6.29-5.88 (m, 3H), 5.47 (dd, 21.51002.0 J = 12.2, 9.8 Hz, 1H), 5.32-5.19 (m, 1H), 5.17-4.85 (m, 3H),4.71-4.50 (m, 1H), 4.32-3.82 (m, 3H), 3.81- 3.37 (m, 6H), 3.33-2.96 (m,10H), 2.91-2.59 (m, 3H), 2.46-2.31 (m, 2H), 2.29-1.81 (m, 6H), 1.80-1.36 (m, 15H), 1.34-0.69 (m, 20H), 0.61 (q, J = 11.5 Hz, 1H). 77H out of85H observed. 32 δ 6.66-6.31 (m, 2H), 6.28-5.88 (m, 3H), 5.52-5.39 23.01015.9 (m, 1H), 5.36-4.83 (m, 4H), 4.61 (d, J = 4.4 Hz, 2H), 4.15-3.85(m, 3H), 3.85-3.50 (m, 5H), 3.47-3.38 (m, 1H), 3.33-3.24 (m, 4H),3.25-2.97 (m, 6H), 2.87- 2.65 (m, 3H), 2.44-2.31 (m, 1H), 2.27-1.79 (m,7H), 1.77-1.48 (m, 15H), 1.47-1.36 (m, 3H), 1.33-1.10 (m, 5H), 1.09-0.65(m, 19H), 0.65-0.53 (m, 1H). 85 out of 87 protons observed. 33 δ 6.48(d, J = 1.6 Hz, 1H), 6.39 (dd, J = 14.3, 11.2 Hz, 13.5 1001.9 1H),6.27-6.05 (m, 3H), 5.46 (dd, J = 14.7, 9.6 Hz, 1H), 5.26 (d, J = 4.5 Hz,1H), 5.12-5.03 (m, 1H), 5.03- 4.90 (m, 2H), 4.58 (dd, J = 4.5, 1.8 Hz,1H), 4.12- 3.85 (m, 4H), 3.81-3.68 (m, 2H), 3.48-3.37 (m, 1H), 3.37-3.10(m, 12H), 2.91-2.66 (m, 2H), 2.45-2.32 (m, 2H), 2.31-1.95 (m, 3H),1.95-1.48 (m, 21H), 1.48- 0.90 (m, 13H), 0.87-0.69 (m, 13H), 0.60 (q, J= 11.7 Hz, 1H). 34 δ 6.50-6.45 (m, 1H), 6.45-6.34 (m, 1H), 6.27-6.0119.6 1001.9 (m, 3H), 5.51-5.41 (m, 1H), 5.29-5.23 (m, 1H), 5.12- 5.05(m, 1H), 5.02-4.90 (m, 2H), 4.66-4.52 (m, 1H), 4.07-3.98 (m, 2H),3.97-3.87 (m, 1H), 3.84- 3.50 (m, 5H), 3.47-3.36 (m, 2H), 3.31-3.25 (m,4H), 3.22-2.97 (m, 6H), 2.88-2.60 (m, 2H), 2.43-2.17 (m, 4H), 2.13-1.97(m, 2H), 1.96-1.78 (m, 4H), 1.76- 1.60 (m, 10H), 1.57-1.13 (m, 11H),1.13-0.94 (m, 7H), 0.91-0.70 (m, 13H), 0.66-0.53 (m, 1H). 35 δ 6.54-6.32(m, 2H), 6.30-6.00 (m, 3H), 5.60-5.37 3.8 987.9 (m, 1H), 5.37-5.18 (m,1H), 5.14-5.01 (m, 1H), 5.01- 4.82 (m, 2H), 4.61-4.54 (m, 1H), 4.09-3.80(m, 4H), 3.73-3.59 (m, 4H), 3.51-3.37 (m, 2H), 3.28- 3.10 (m, 9H),2.91-2.63 (m, 2H), 2.47-2.16 (m, 2H), 2.14-1.95 (m, 3H), 1.95-1.47 (m,19H), 1.46-0.92 (m, 13H), 0.91-0.69 (m, 13H), 0.67-0.53 (m, 1H). 36 δ6.51-6.34 (m, 2H), 6.29-6.04 (m, 3H), 5.46 (dd, 20.4 986.0 J = 13.6, 9.6Hz, 1H), 5.31-5.23 (m, 1H), 5.16-4.86 (m, 3H), 4.65-4.54 (m, 1H),4.13-3.85 (m, 3H), 3.81- 3.67 (m, 1H), 3.51-3.39 (m, 1H), 3.33-3.04 (m,11H), 2.86-2.69 (m, 2H), 2.49-2.16 (m, 4H), 2.15- 1.47 (m, 25H),1.46-1.12 (m, 7H), 1.11-0.68 (m, 19H), 0.67-0.57 (m, 1H). 37 δ 6.61-6.39(m, 2H), 6.21-5.89 (m, 3H), 5.70-5.54 3.0 985.9 (m, 1H), 5.37-5.28 (m,1H), 5.27-5.07 (m, 2H), 5.03- 4.91 (1H), 4.67-4.58 (m, 1H), 4.12-3.88(m, 3H), 3.84-3.70 (m, 1H), 3.64-3.49 (m, 1H), 3.33-2.99 (m, 11H),2.85-2.69 (m, 2H), 2.59-2.54 (m, 1H), 2.47- 2.40 (m, 1H), 2.35-2.12 (m,2H), 2.05-1.78 (m, 6H), 1.77-1.46 (m, 17H), 1.45-1.06 (m, 9H), 1.05-0.67 (m, 19H), 0.64-0.53 (m, 1H). 38 δ 6.50 (s, 1H), 6.45-6.34 (m, 1H),6.29-6.07 (m, 2H), 8.7 1046.0 5.46 (dd, J = 14.7, 9.6 Hz, 1H), 5.33-5.16(m, 1H), 5.14-5.04 (m, 1H), 5.01-4.90 (m, 2H), 4.52-4.44 (m, 1H),4.08-3.90 (m, 2H), 3.82-3.53 (m, 5H), 3.53- 3.40 (m, 5H), 3.31-3.20 (m,5H), 3.20-2.92 (m, 8H), 2.86-2.61 (m, 2H), 2.43-2.31 (m, 2H), 2.30- 2.16(m, 1H), 2.16-2.00 (m, 2H), 2.00-1.78 (m, 5H), 1.78-1.34 (m, 16H),1.34-1.18 (m, 4H), 1.18-0.90 (m, 8H), 0.90-0.54 (m, 14H). 39 δ 6.54-6.31(m, 2H), 6.30-6.05 (m, 3H), 5.46 (dd, 8.2 971.9 J = 12.4, 10.2 Hz, 1H),5.31-5.24 (m, 1H), 5.14-4.86 (m, 3H), 4.65-4.54 (m, 1H), 4.20-3.92 (m,3H), 3.83- 3.74 (m, 1H), 3.52-3.40 (m, 1H), 3.34-3.32 (m, 3H), 3.30-2.91(m, 7H), 2.90-2.64 (m, 3H), 2.45- 2.05 (m, 5H), 2.04-1.82 (m, 3H),1.80-1.47 (m, 11H), 1.46-1.13 (m, 7H), 1.11-0.69 (m, 19H), 0.66-0.55 (m,1H), 0.52-0.31 (m, 2H), 0.18-0.00 (m, 2H). 79H out of 83H observed. 40 δ6.48-6.44 (m, 1H), 6.39 (dd, J = 14.4, 11.2 Hz, 1H), 7.6 1000.06.27-6.14 (m, 1H), 6.14-6.06 (m, 2H), 5.45 (dd, J = 14.6, 9.7 Hz, 1H),5.26 (d, J = 4.6 Hz, 1H), 5.11 5.05 (m, 1H), 5.01-4.90 (m, 2H), 4.59 (d,J = 4.5 Hz, 1H), 4.11-3.98 (m, 2H), 3.95 (d, J = 4.5 Hz, 1H), 3.75 3.69(m, 1H), 3.48 3.41 (m, 1H), 3.32 (s, 3H), 3.25-3.05 (m, 7H), 2.95 (dd, J= 9.2, 6.8 Hz, 1H), 2.88-2.78 (m, 1H), 2.78-2.65 (m, 1H), 2.43-2.29 (m,2H), 2.29- 2.15 (m, 1H), 2.14-1.94 (m, 3H), 1.94-1.78 (m, 3H), 1.77-1.71(m, 3H), 1.71-1.59 (m, 9H), 1.58-1.34 (m, 9H), 1.32-1.09 (m, 7H),1.08-0.90 (m, 7H), 0.90- 0..69 (m, 13H), 0.60 (q, J = 12.0 Hz, 1H). 41 δ6.53-6.34 (m, 2H), 6.28-6.05 (m, 3H), 5.46 (dd, 22.1 1022.0 J = 12.4,9.0 Hz, 1H), 5.32-5.24 (m, 1H), 5.09 (d, J = 10.2 Hz, 1H), 5.05-4.87 (m,2H), 4.65-4.55 (m, 1H), 4.09-3.68 (m, 4H), 3.51-3.39 (m, 1H), 3.35-3.32(m, 3H), 3.26-3.12 (m, 7H), 2.95-2.55 (m, 5H), 2.46- 1.96 (m, 8H),1.95-1.13 (m, 23H), 1.12-0.68 (m, 19H), 0.61 (dd, J = 12.4, 10.0 Hz,1H). 82H out of 83H observed. ¹⁹F NMR (376 MHz, DMSO-d₆) δ −81.3 (d, J =203 Hz), −91.3 (d, J = 203 Hz). 42 δ 6.51 (d, J = 1.4 Hz, 1H), 6.38 (dd,J = 14.5, 11.2 Hz, 22.3 1029.9 1H), 6.27-6.05 (m, 3H), 5.45 (dd, J =14.6, 9.6 Hz, 1H), 5.36-5.24 (m, 1H), 5.07 (d, J = 10.1 Hz, 1H), 5.01-4.87 (m, 2H), 4.38-4.30 (m, 1H), 4.13-3.95 (m, 3H), 3.83-3.71 (m, 1H),3.63-3.39 (m, 6H), 3.33- 3.09 (m, 6H), 3.06-2.90 (m, 4H), 2.85-2.62 (m,1H), 2.44-2.30 (m, 2H), 2.30-2.14 (m, 1H), 2.15-1.77 (m, 6H), 1.77-1.46(m, 14H), 1.46-1.13 (m, 7H), 1.13- 0.89 (m, 9H), 0.89-0.69 (m, 13H),0.64 (q, J = 11.9 Hz, 1H), 0.52-0.37 (m, 2H), 0.18-0.02 (m, 2H). 43 δ6.57 (s, 1H), 6.51-6.36 (m, 1H), 6.25-6.07 (m, 2H), 9.0 1029.8 6.07-5.96(m, 1H), 5.66-5.53 (m, 1H), 5.34-5.05 (m, 3H), 5.02-4.95 (m, 1H),4.41-4.22 (m, 1H), 4.07- 3.87 (m, 3H), 3.79 (dd, J = 9.6, 2.2 Hz, 1H),3.75- 3.66 (m, 1H), 3.59-3.40 (m, 6H), 3.30-2.88 (m, 7H), 2.83-2.66 (m,2H), 2.55 (d, J = 9.4 Hz, 1H), 2.38- 1.79 (m, 7H), 1.79 (s, 23H),1.18-0.54 (m, 23H), 0.42 (dt, J = 7.4, 2.2 Hz, 2H), 0.19-−0.04 (m, 2H).44 δ 6.49 (d, J = 1.5 Hz, 1H), 6.46-6.33 (m, 1H), 6.27- 7.6 1043.9 6.06(m, 3H), 5.45 (dd, J = 14.6, 9.7 Hz, 1H), 5.28 (d, J = 13.6 Hz, 1H),5.08 (d, J = 10.2 Hz, 1H), 5.01-4.89 (m, 2H), 4.39-4.30 (m, 1H),4.10-3.93 (m, 3H), 3.79- 3.66 (m, 1H), 3.62-3.39 (m, 7H), 3.32-2.89 (m,10H), 2.79-2.62 (m, 1H), 2.49-2.31 (m, 5H), 2.31- 2.16 (m, 1H),2.15-1.48 (m, 26H), 1.46-0.90 (m, 12H), 0.89-0.57 (m, 14H). 45 δ 6.50(s, 1H), 6.47-6.32 (m, 1H), 6.27-6.07 (m, 3H), 11.4 1029.9 5.45 (dd, J =14.4, 9.9 Hz, 1H), 5.35-5.24 (m, 1H), 5.07 (d, J = 10.1 Hz, 1H),5.01-4.89 (m, 2H), 4.56- 4.44 (m, 1H), 4.10-3.90 (m, 2H), 3.78-3.66 (m,1H), 3.55-3.42 (m, 5H), 3.34-3.22 (m, 4H), 3.22-2.91 (m, 8H), 2.87-2.58(m, 2H), 2.49-2.16 (m, 4H), 2.15- 1.77 (m, 9H), 1.75 (s, 2H), 1.73-1.46(m, 14H), 1.46- 1.35 (m, 2H), 1.35-0.91 (m, 11H), 0.89-0.69 (m, 13H),0.69-0.57 (m, 1H). 46 δ 6.55-6.33 (m, 2H), 6.29-6.06 (m, 3H), 5.46 (dd,12.7 1001.9 J = 12.3, 10.1 Hz, 1H), 5.36-5.27 (m, 1H), 5.16-4.86 (m,3H), 4.49 (d, J = 2.0 Hz, 1H), 4.08-3.76 (m, 4H), 3.56-3.38 (m, 5H),3.34-2.93 (m, 11H), 2.77-2.67 (m, 1H), 2.45-2.32 (m, 2H), 2.28-2.16 (m,1H), 2.14- 1.87 (m, 4H), 1.86-1.46 (m, 15H), 1.45-1.10 (m, 8H),1.09-0.91 (m, 7H), 0.90-0.68 (m, 11H), 0.67- 0.59 (m, 1H), 0.54-0.24 (m,4H). 47 δ 6.69-6.36 (m, 2H), 6.32-5.92 (m, 3H), 5.68-5.41 2.8 1001.9 (m,1H), 5.35-5.04 (m, 3H), 5.02-4.87 (m, 1H), 4.52- 4.44 (m, 1H), 4.11-3.75(m, 4H), 3.63-3.37 (m, 5H), 3.34-3.28 (m, 4H), 3.21-3.10 (m, 3H), 3.09-2.90 (m, 3H), 2.84-2.64 (m, 2H), 2.57-2.52 (m, 1H), 2.41-2.04 (m, 3H),2.03-1.82 (m, 3H), 1.81-1.17 (m, 20H), 1.16-0.68 (m, 19H), 0.67-0.54 (m,1H), 0.52-0.15 (m, 4H). 83H out of 85H observed. 48 δ 6.57-5.93 (m, 5H),5.58-5.36 (m, 1H), 5.33-4.86 10.0 1043.9 (m, 4H), 4.35-3.68 (m, 13H),3.20-2.95 (m, 7H), 2.83- 2.62 (m, 1H), 2.45-2.32 (m, 2H), 2.16-1.45 (m,19H), 1.45-0.68 (m, 30H), 0.62 (q, J = 11.8 Hz, 1H), 0.54-0.23 (m, 4H).49 δ 6.52 (s, 1H), 6.47-6.34 (m, 1H), 6.29-6.07 (m, 3H), 10.4 1071.95.55 (dd, J = 12.4, 10.2 Hz, 1H), 5.36-5.28 (m, 1H), 5.14-4.89 (m, 3H),4.28-3.94 (m, 7H), 3.78-3.68 (m, 1H), 3.42 (d, J = 7.0 Hz, 1H),3.32-2.96 (m, 12H), 2.83-2.64 (m, 2H), 2.47-2.16 (m, 4H), 2.15-1.90 (m,6H), 1.89-1.47 (m, 18H), 1.46-1.12 (m, 11H), 1.11-0.68 (m, 18H),0.65-0.54 (m, 1H). 50 δ 6.48 (s, 1H), 6.41-6.33 (m, 1H), 6.26-6.05 (m,3H), 6.7 1057.9 5.47 (dd, J = 12.4, 10.2 Hz, 1H), 5.29-5.23 (m, 1H),5.12-4.89 (m, 3H), 4.28-3.92 (m, 7H), 3.82-3.75 (m, 1H), 3.49-3.39 (m,1H), 3.31-3.07 (m, 9H), 3.06- 2.94 (m, 3H), 2.76-2.66 (m, 1H), 2.45-2.29(m, 2H), 2.27-2.16 (m, 1H), 2.13-1.82 (m, 6H), 1.78- 1.51 (m, 13H),1.45-1.15 (m, 10H), 1.09-0.68 (m, 20H), 0.67-0.55 (m, 1H), 0.49-0.36 (m,2H), 0.20- 0.04 (m, 2H). 51 δ 6.58-6.34 (m, 2H), 6.27-5.97 (m, 3H),5.68-5.55 2.2 1057.9 (m, 1H), 5.29-5.23 (m, 1H), 5.17-5.06 (m, 2H),5.02- 4.90 (m, 1H), 4.24-3.90 (m, 7H), 3.79 (d, J = 7.8 Hz, 1H), 3.56(d, J = 8.0 Hz, 1H), 3.29-2.92 (m, 12H), 2.81- 2.73 (m, 1H), 2.59-2.52(m, 1H), 2.34-2.20 (m, 1H), 2.19-1.85 (m, 5H), 1.76-1.45 (m, 14H), 1.43-1.06 (m, 12H), 1.04-0.69 (m, 19H), 0.68-0.54 (m, 1H), 0.49-0.34 (m, 2H),0.20-0.00 (m, 2H). 52 δ 6.48-6.35 (m, 2H), 6.31-6.06 (m, 3H), 5.47 (dd,28.6 1015.9 J = 14.8, 9.6 Hz, 1H), 5.27 (d, J = 4.4 Hz, 1H), 5.09 (d, J= 10.2 Hz, 1H), 5.01-4.89 (m, 2H), 4.36-4.23 (m, 1H), 4.06-3.77 (m, 4H),3.62-3.37 (m, 7H), 3.27- 3.11 (m, 5H), 3.10-2.87 (m, 4H), 2.78-2.65 (m,1H), 2.45-1.84 (m, 5H), 1.84-1.16 (m, 23H), 1.16-0.90 (m, 10H),0.91-0.57 (m, 13H), 0.55-0.24 (m, 4H). 53 δ 6.64 (s, 1H), 6.56-6.38 (m,1H), 6.31-6.03 (m, 3H), 5.4 1015.9 5.71-5.58 (m, 1H), 5.44-5.10 (m, 3H),5.01-4.83 (m, 1H), 4.35-4.20 (m, 1H), 4.11-3.97 (m, 1H), 3.97- 3.77 (m,3H), 3.59-3.37 (m, 6H), 3.22-3.11 (m, 9H), 2.87-2.58 (m, 2H), 2.59-2.51(m, 1H), 2.42- 2.21 (m, 1H), 2.21-1.81 (m, 5H), 1.80-1.18 (m, 24H),1.17-0.60 (m, 20H), 0.53-0.20 (m, 4H). 54 δ 6.77-6.52 (m, 1H), 6.44-6.32(m, 1H), 6.27-6.01 19.1 1015.8 (m, 2H), 5.45 (dd, J = 14.7, 9.7 Hz, 1H),5.37-5.20 (m, 1H), 5.10-5.00 (m, 1H), 5.00-4.89 (m, 2H), 4.52 (t, J =5.3 Hz, 1H), 4.12-3.96 (m, 3H), 3.82-3.68 (m, 1H), 3.58-3.39 (m, 5H),3.35-3.21 (m, 4H), 3.22- 3.09 (m, 4H), 3.09-2.89 (m, 4H), 2.79-2.68 (m,1H), 2.41-2.28 (m, 2H), 2.28-2.14 (m, 1H), 2.14-1.79 (m, 6H), 1.75 (s,2H), 1.72-1.45 (m, 11H), 1.45-1.33 (m, 2H), 1.33-0.87 (m, 14H),0.87-0.56 (m, 13H), 0.48-0.36 (m, 2H), 0.18-0.00 (m, 2H). 55 ^(c) δ6.46-6.34 (m, 2H), 6.30-6.05 (m, 3H), 5.44 (dd, 14.5 1001.8 C28 isomer J= 14.3, 9.8 Hz, 1H), 5.02 (d, J = 4.7 Hz, 2H), 4.94 (d, (C28 S J = 7.6Hz, 1H), 4.58 (d, J = 4.4 Hz, 1H), 4.09-3.96 (m, configuration) 2H),3.88-3.55 (m, 5H), 3.31 (s, 13H), 2.86-2.60 (m, 3H), 2.45-2.21 (m, 3H),2.19-1.98 (m, 2H), 1.98- 1.38 (m, 20H), 1.38-1.07 (m, 7H), 1.07-0.87 (m,6H), 0.87-0.66 (m, 13H), 0.66-0.47 (m, 1H). 56 ^(e) δ 6.50 (s, 1H),6.45-6.34 (m, 1H), 6.27-6.07 (m, 3H), 1062.0 5.46 (dd, J = 14.7, 9.7 Hz,1H), 5.33-5.22 (m, 1H), 5.08 (d, J = 10.2 Hz, 1H), 5.00-4.90 (m, 2H),4.32- 4.15 (m, 2H), 4.15-4.04 (m, 2H), 4.05-3.93 (m, 2H), 3.82-3.71 (m,1H), 3.47-3.29 (m, 7H), 3.28-3.19 (m, 6H), 3.19-3.09 (m, 5H), 3.08-2.98(m, 1H), 2.77- 2.68 (m, 1H), 2.42-2.30 (m, 2H), 2.28-2.16 (m, 1H),2.14-2.06 (m, 1H), 2.03-1.81 (m, 4H), 1.74 (s, 3H), 1.70-1.47 (m, 10H),1.45-1.35 (m, 2H), 1.34- 1.09 (m, 9H), 1.08-0.87 (m, 6H), 0.89-0.70 (m,13H), 0.61 (q, J = 12.1 Hz, 1H). 57 ^(e) δ 12.68 (s, 1H), 6.65 (ddd, J =15.7, 8.1, 1.8 Hz, 1H), 24.4 1033.9 6.60-6.33 (m, 2H), 6.33-6.01 (m,3H), 5.55 (dd, J = 14.6, 8.6 Hz, 1H), 5.26 (d, J = 4.6 Hz, 1H),5.23-5.15 (m, 1H), 4.38-4.03 (m, 3H), 3.94 (dd, J = 7.0, 4.4 Hz, 1H),3.81-3.67 (m, 3H), 3.66-3.55 (m, 1H), 3.55- 3.45 (m, 1H), 3.43-3.35 (m,2H), 3.31-3.17 (m, 8H), 3.15 (s, 3H), 3.13-3.07 (m, 1H), 3.06-2.94 (m,1H), 2.80-2.68 (m, 2H), 2.42-2.34 (m, 1H), 2.31-2.20 (m, 1H), 2.18-1.89(m, 5H), 1.77-1.38 (m, 14H), 1.38- 1.07 (m, 8H), 1.06-0.87 (m, 16H),0.87-0.75 (m, 1H), 0.74-0.65 (m, 3H). 58 ^(e) δ 6.66 (dd, J = 15.6, 8.0Hz, 1H), 6.48 (dd, J = 17.2, 1.6 71 1106.6 Hz, 1H), 6.41 (d, J = 12.1Hz, 1H), 6.29-6.05 (m, 4H), 5.65-5.51 (m, 1H), 5.27-5.17 (m, 2H), 4.57(d, J = 4.3 Hz, 1H), 4.52-4.46 (m, 1H), 4.33-4.07 (m, 3H), 3.99-3.91 (m,1H), 3.75 (d, J = 7.0 Hz, 2H), 3.67- 3.53 (m, 2H), 3.32-3.27 (m, 3H),3.21-3.11 (m, 4H), 3.09-3.01 (m, 3H), 2.86-2.71 (m, 3H), 2.47-2.19 (m,3H), 2.18-1.85 (m, 5H), 1.79-1.41 (m, 18H), 1.37- 1.09 (m, 8H),1.06-0.94 (m, 10H), 0.91 (d, J = 6.6 Hz, 3H), 0.88-0.78 (m, 1H),0.76-0.62 (m, 4H)For Table 4 and Table 5: ^(a)Reaction performed according to GeneralMethod 3 unless otherwise noted. Time reported is the time stirred at 0°C. Where reaction was incomplete at end of working day, reaction wasstored at −20° C. overnight, then stirring at 0° C. continued, asexcessive stirring at 0° C. could lead to degradation; ^(b)Additioncarried out at −40° C., then stored at −20° C. for 7 days, after whichreaction was complete; ^(c)C-28 epimer, from Intermediate H;^(d)R-isomer not isolated; ^(e)See specific example for syntheticdetails; ^(f)The NMR characterization data shown in the examplescorrespond only to the major equilibrium form observed under thereported deutero solvent conditions; ^(&)denotes the stereochemicalconfiguration at C16.

General Method 4 (C-16 Ethers) Example 25 Synthesis of Compound 60

To a stirred solution of Intermediate C (600 mg; 0.60 mmol) andcyclopropylmethanol (1.76 g; 24.4 mmol) in DCM (24 mL) at −40° C. wasadded para-toluenesulfonic acid monohydrate (570 mg; 3.00 mmol). Thereaction mixture was allowed to warm to 0° C. and stirred at thistemperature for 0.5 h. Amberlyst A21 free base (2.7 g) was added, andafter stirring for 5 min, the mixture was filtered and washed with DCM(100 mL). The combined filtrate and washings were washed with water(5×25 mL), then dried (Na₂SO₄), filtered, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(EtOAc in hexanes, 20-100%), then by HPLC (method 1) to give Compound 60(41.5 mg, 10.9%) as a flocculent solid.

General Method 5 (C-16 Ethers) Example 26 Synthesis of Compound 61

To a stirred solution of Intermediate C (150 mg; 0.15 mmol) in2-methoxyethanol (3 mL) at room temperature was addedpara-toluenesulfonic acid monohydrate (2.8 mg; 0.015 mmol). The reactionmixture was stirred for 4.5 h., then diluted with EtOAc (5 mL) andsaturated sodium bicarbonate solution that had been adjusted to pH 7with 30% H₂SO₄ in water (4 mL). After stirring for 5 min, the layerswere separated and the aqueous layer extracted with ethyl acetate (2×4mL). The combined organics were washed with water (4 mL) and brine (4mL), then dried (Na₂SO₄), and concentrated under reduced pressure. Theresidue was purified by HPLC (method 1) to give Compound 61 (31.1 mg,19.9%) as a flocculent solid.

General Method 6 (C-16 Ethers) Example 27 Synthesis of Compound 66

To a stirred solution of Intermediate C (150 mg; 0.15 mmol) and2-[2-(2-methoxyethoxy)ethoxy]ethan-1-ol (242 mg, 1.47 mmol) in DCM (3.5mL) at rt was added a 0.1M solution of FeCl₃ in Et2O (140 μL, 0.015mmol) and the mixture stirred for 5 h. After storing overnight at −20°C. further 0.1M FeCl₃ in Et2O (193 μL, 0.015 mmol) was added, andstirring continued for 5 h. Saturated sodium bicarbonate solution (3 mL)was added, and the mixture extracted with DCM (3×5 mL). The combinedorganics were washed with water (3 mL) and brine (3 mL) and purified bysilica gel column chromatography (50-100% EtOAc in hexanes then 0-2%MeOH in EtOAc) followed by HPLC (method 1) to give Compound 66 (16.0 mg,9.5%) as a flocculent solid.

TABLE 6 Compounds of Formula JJJ with corresponding R substituents.Compounds of Table 6 were synthesized using the methods describedherein, e.g., the procedures of Examples 25-27, and employing theappropriate reagents. C16 RT/ Compound Method R R/S mins t/h^(a) 59 [IntC] Int C

S  60 4

S^(b) 4.98 3 61 5

S^(b) 3.69 4.5 62 4

S  5.89 4 63 4

R  5.72 4 64 4

S^(b) 4.69 1.5 65 6

S^(e) 3.33 9 66 6

S^(e) 3.28 10  67 ^(c,d) 7

S  2.22 24  68 ^(d) 6

S  2.47 16  69 ^(d) 6

R  2.77 16 70 6

S  2.26 13 71 6

R^(f) 2.44 13 72 6

S  2.25 13 73 6

R^(f) 2.44 13

TABLE 7 Characterization data for compounds of Table 6 Yield CompoundNMR ¹H NMR (400 MHz, DMSO-d₆)^(g) (%) [M + NH₄]⁺ 60 δ 6.49 (d, J = 1.6Hz, 1H), 6.41-6.33 (m, 1H), 6.28-5.99 10.9 1091.9 (m, 3H), 5.45 (dd, J =12.6, 10.1 Hz, 1H), 5.32-5.23 (m, 1H), 5.12-4.84 (m, 3H), 4.15-3.92 (m,3H), 3.82-3.74 (m, 1H), 3.62-3.37 (m, 3H), 3.34-3.22 (m, 4H), 3.19- 3.05(m, 5H), 3.04-2.91 (m, 6H), 2.84-2.62 (m, 2H), 2.43-2.29 (m, 2H),2.22-1.78 (m, 8H), 1.72-1.45 (m, 12H), 1.44-1.07 (m, 7H), 1.06-0.69 (m,19H), 0.69- 0.58 (m, 1H), 0.52-0.34 (m, 2H), 0.17-0.00 (m, 2H). 87H outof 91H observed. 61 δ 6.50 (d, J = 1.5 Hz, 1H), 6.45-6.35 (m, 1H),6.31-6.00 19.9 1096.0 (m, 3H), 5.46 (dd, J = 14.7, 9.6 Hz, 1H),5.35-5.24 (m, 1H), 5.15-4.89 (m, 3H), 4.11-3.89 (m, 3H), 3.85-3.75 (m,1H), 3.66-3.50 (m, 2H), 3.48-3.36 (m, 3H), 3.32- 3.06 (m, 13H),3.05-2.94 (m, 5H), 2.87-2.64 (m, 2H), 2.45-1.81 (m, 9H), 1.80-1.45 (m,13H), 1.44-1.18 (m, 6H), 1.17-0.71 (m, 19H), 0.68-0.57 (m, 1H). 87H outof 91H observed. 62 δ 6.50 (d, J = 1.6 Hz, 1H), 6.46-6.32 (m, 1H),6.29-6.03 8.2 1106.0 (m, 3H), 5.45 (dd, J = 14.7, 9.7 Hz, 1H), 5.30 (dd,J = 8.7, 4.7 Hz, 1H), 5.08 (d, J = 10.3 Hz, 1H), 4.99-4.89 (m, 2H),4.10-3.93 (m, 3H), 3.77-3.66 (m, 1H), 3.65-3.38 (m, 5H), 3.29-2.90 (m,14H), 2.80-2.58 (m, 2H), 2.47-2.16 (m, 3H), 2.16-1.47 (m, 29H),1.45-0.90 (m, 12H), 0.89- 0.55 (m, 14H). 63 δ 6.62 (s, 1H), 6.51-6.37(m, 1H), 6.25-5.98 (m, 3H), 4.9 1106.0 5.66-5.53 (m, 1H), 5.35-5.27 (m,1H), 5.24 (d, J = 10.2 Hz, 1H), 5.15-5.07 (m, 1H), 5.01-4.95 (m, 1H),4.08- 3.89 (m, 4H), 3.81-3.73 (m, 1H), 3.64-3.49 (m, 4H), 3.30-2.89 (m,15H), 2.81-2.64 (m, 2H), 2.52-2.40 (m, 2H), 2.33-2.11 (m, 2H), 2.04-1.19(m, 33H), 1.18-0.55 (m, 20H). 64 δ 6.62-6.27 (m, 2H), 6.21-5.92 (m, 3H),5.47 (dd, J = 14.2 1077.9 12.6, 10.1 Hz, 1H), 5.33-4.89 (m, 4H),4.18-3.78 (m, 4H), 3.67-3.39 (m, 3H), 3.34-2.90 (m, 16H), 2.78-2.66 (m,1H), 2.45-2.05 (m, 4H), 2.04-1.45 (m, 18H), 1.44- 1.09 (m, 7H),1.08-0.58 (m, 18H), 0.54-0.19 (m, 4H). 85H out of 89H observed. 65 δ6.49-6.33 (m, 2H), 6.29-6.02 (m, 4H), 5.46 (dd, J = 10.5 1139.8 14.5,9.6 Hz, 1H), 5.30-5.17 (m, 2H), 5.14-5.04 (m, 1H), 5.01-4.91 (m, 2H),4.11-3.90 (m, 3H), 3.84-3.74 (m, 1H), 3.65-3.39 (m, 10H), 3.29-3.20 (m,5H), 3.20-3.07 (m, 6H), 3.08-2.92 (m, 6H), 2.84-2.61 (m, 1H), 2.47- 1.81(m, 8H), 1.79-1.46 (m, 12H), 1.46-0.90 (m, 17H), 0.90-0.57 (m, 14H). 66δ 6.49-6.33 (m, 2H), 6.31-6.01 (m, 3H), 5.46 (dd, J = 9.5 1183.7 14.6,9.6 Hz, 1H), 5.30-5.21 (m, 1H), 5.15-5.06 (m, 1H), 5.01-4.91 (m, 2H),4.12-3.89 (m, 3H), 3.86-3.71 (m, 1H), 3.67-3.38 (m, 16H), 3.27-3.09 (m,11H), 3.08- 2.91 (m, 5H), 2.85-2.63 (m, 2H), 2.44-1.80 (m, 9H),1.81-1.48 (m, 16H), 1.44-0.90 (m, 12H), 0.90-0.56 (m, 14H). 67 ^(c, d) δ6.82-6.44 (m, 1H), 6.44-6.35 (m, 1H), 6.30-6.06 (m, 1.2 1081.8 3H), 5.46(dd, J = 14.7, 9.5 Hz, 1H), 5.30-5.24 (m, 1H), 5.13-5.06 (m, 1H),5.00-4.90 (m, 2H), 4.54-4.49 (m, 1H), 4.10-3.98 (m, 2H), 4.00-3.93 (m,1H), 3.81-3.70 (m, 1H), 3.65-3.52 (m, 2H), 3.48-3.40 (m, 3H), 3.30- 3.08(m, 12H), 3.07-2.98 (m, 2H), 2.96 (s, 3H), 2.83- 2.69 (m, 1H), 2.55-2.51(m, 1H), 2.44-2.33 (m, 1H), 2.28-2.17 (m, 1H), 2.14-2.06 (m, 1H),2.06-1.83 (m, 6H), 1.74 (s, 3H), 1.71-1.46 (m, 11H), 1.45-0.92 (m, 13H),0.91-0.59 (m, 14H). 68 ^(d) δ 6.48-6.41 (m, 1H), 6.41-6.34 (m, 1H),6.27-6.02 (m, 4.9 1095.8 3H), 5.45 (dd, J = 14.5, 9.6 Hz, 1H), 5.30-5.23(m, 1H), 5.12-5.05 (m, 1H), 5.00-4.96 (m, 1H), 4.96-4.90 (m, 1H),4.39-4.32 (m, 1H), 4.05-3.99 (m, 2H), 3.99-3.93 (m, 1H), 3.76-3.68 (m,1H), 3.66-3.52 (m, 3H), 3.48- 3.38 (m, 3H), 3.29-3.22 (m, 3H), 3.18-3.08(m, 8H), 3.07-2.94 (m, 5H), 2.87-2.69 (m, 1H), 2.43-2.30 (m, 2H),2.27-2.15 (m, 1H), 2.14-2.00 (m, 2H), 1.99-1.78 (m, 6H), 1.75 (s, 3H),1.71-1.47 (m, 12H), 1.47-1.35 (m, 2H), 1.34-0.89 (m, 11H), 0.89-0.53 (m,14H). 69 ^(d) δ 6.60-6.51 (m, 1H), 6.51-6.35 (m, 1H), 6.31-6.00 (m, 8.81095.8 3H), 5.64 (dd, J = 14.3, 7.9 Hz, 1H), 5.35-5.07 (m, 3H),5.03-4.93 (m, 1H), 4.54-4.33 (m, 1H), 4.08-3.94 (m, 2H), 3.91 (d, J =4.7 Hz, 1H), 3.83-3.66 (m, 1H), 3.65- 3.51 (m, 3H), 3.50-3.40 (m, 2H),3.38-3.32 (m, 4H), 3.27-3.00 (m, 9H), 3.00-2.95 (m, 4H), 2.84-2.70 (m,1H), 2.60-2.53 (m, 1H), 2.31-2.21 (m, 1H), 2.20-2.07 (m, 1H), 2.06-1.81(m, 6H), 1.78-1.46 (m, 16H), 1.46- 1.20 (m, 6H), 1.19-0.91 (m, 11H),0.91-0.57 (m, 11H). 70 6.48-6.33 (m, 2H), 6.27-6.08 (m, 3H), 5.46 (dd, J= 14.8, 9.9 1125.8 9.5 Hz, 1H), 5.30-5.23 (m, 1H), 5.13-5.06 (m, 1H),5.01- 4.91 (m, 2H), 4.59-4.51 (m, 1H), 4.09-3.98 (m, 2H), 3.98-3.92 (m,1H), 3.83-3.72 (m, 1H), 3.64-3.37 (m, 11H), 3.27-3.09 (m, 9H), 3.07-2.92(m, 6H), 2.82-2.69 (m, 1H), 2.44-2.35 (m, 1H), 2.28-2.15 (m, 1H), 2.14-1.80 (m, 8H), 1.76-1.46 (m, 12H), 1.46-1.34 (m, 2H), 1.34-1.19 (m, 4H),1.19-0.91 (m, 9H), 0.91-0.53 (m, 14H). 71 6.94-6.62 (m, 2H), 6.55-6.26(m, 3H), 5.94-5.70 (m. 9.5 1125.8 1H), 5.63-5.47 (m, 2H), 5.47-5.34 (m,1H), 5.31-5.19 (m, 1H), 4.89-4.78 (m, 1H), 4.38-4.17 (m, 3H), 4.15- 4.02(m, 1H), 3.94-3.81 (m, 3H), 3.81-3.73 (m, 4H), 3.73-3.62 (m, 4H),3.51-3.37 (m, 7H), 3.39-3.20 (m, 7H), 3.19-2.89 (m, 2H), 2.73-2.38 (m,1H), 2.35-2.09 (m, 6H), 2.09-1.74 (m, 15H), 1.74-1.47 (m, 6H), 1.47-1.19 (m, 9H), 1.19-0.83 (m, 14H). 72 6.96-6.34 (m, 2H), 6.31-6.07 (m,3H), 5.47 (dd, J = 14.6, 11.3 1169.9 9.6 Hz, 1H), 5.31-5.25 (m, 1H),5.13-5.06 (m, 1H), 5.03- 4.91 (m, 2H), 4. 59-4.55 (m, 1H), 4.10-3.99 (m,2H), 3.99-3.93 (m, 1H), 3.84-3.73 (m, 1H), 3.67-3.56 (m, 2H), 3.56-3.46(m, 10H), 3.46-3.39 (m, 3H), 3.26-3.09 (m, 9H), 3.08-2.98 (m, 2H),2.98-2.95 (m, 4H), 2.84- 2.69 (m, 1H), 2.44-2.33 (m, 2H), 2.30-2.18 (m,1H), 2.14-2.01 (m, 2H), 2.01-1.85 (m, 5H), 1.75 (s, 3H), 1.72- 1.51 (m,9H), 1.46-1.36 (m, 2H), 1.35-1.20 (m, 4H), 1.20-1.10 (m, 2H), 1.10-0.92(m, 7H), 0.92-0.72 (m, 13H), 0.65 (q, J = 11.9 Hz, 1H). 73 6.59-6.52 (m,1H), 6.50-6.33 (m, 1H), 6.28-6.01 (m, 8.1 1169.9 3H), 5.67-5.42 (m, 1H),5.29-5.06 (m, 3H), 5.04-4.92 (m, 1H), 4.61-4.50 (m, 2H), 4.10-3.90 (m,3H), 3.89- 3.74 (m, 1H), 3.74-3.38 (m, 15H), 3.33-3.22 (m, 1H),3.24-3.08 (m, 7H), 3.10-2.91 (m, 5H), 2.81-2.63 (m, 2H), 2.58-2.52 (m,1H), 2.43-1.81 (m, 9H), 1.81-1.47 (m, 16H), 1.46-1.19 (m, 3H), 1.19-0.90(m, 8H), 0.90- 0.54 (m, 14H).For Table 6 and Table 7: ^(a)Time stirred at 0° C. (Method 1) or roomtemperature (Methods 3 and 4). Where reaction was incomplete at end ofworking day, reaction was stored at 20° C. overnight, then stirring atlisted temperature continued; ^(b)Isolated S-isomer contained up to 10%C-16 R isomer; ^(c)A third addition of FeCl₃ solution was required forcomplete conversion. ^(d)Reaction mixture cooled in ice bath for firstaddition of FeCl₃ solution; ^(e)˜3:1 mix S:R at C-16; ^(f)˜2:3 mix S:RatC-16; ^(g)The NMR characterization data shown in the examples correspondonly to the major equilibrium form observed under the reporteddeuterated solvent conditions.

Differential pharmacology of compounds described herein may be observedin different cell or tissue types depending on (1) the relativeabundance of FKBP homologs in these cells/tissues and (2) thespecificity of binding to these different FKBP homologs (Mol. Cell Biol.(2013) 33: 1357-1367). Various FKBP homologs are used in the followingexamples.

Example 28

SPR Assay to Determine Binding Affinity to FKBP12.

Biotinylated avi-FKBP12 was immobilized on a streptavidin chip (CytivaSeries S SA) using a Biacore 8K or 8k+ (Cytiva). To achieve animmobilization level of 1000 RU, 2 μg/ml biotinylated avi-FKBP12 wereinjected for 100 sec at a flow rate of 10 μl/min. Rapalogs were dilutedin DMSO to 100× working concentration. Each Rapalog was 100-fold dilutedin 50 mM HEPES pH 7.5, 150 mM NaCl, 2 mM MgCl₂, 1 mM DTT, 0.05% Tween-20and a serial dilution prepared (9 concentrations, 3-fold dilutions,0.08-500 nM). Rapamycin was used as reference sample (9 concentrations,3-fold dilutions, 0.02-100 nM). The compound dilutions were theninjected at 100 uL/min for 120 seconds contact time in sequence withincreasing concentrations. Dissociation was monitored for 3600 seconds.50 mM HEPES pH 7.5, 150 mM NaCl, 2 mM MgCl₂, 1 mM DTT, 0.05% Tween-20,1% DMSO was used as running buffer. The single-cycle kinetics data werefit to a 1:1 binding model to measure the association rate ka (1/Ms),the dissociation rate kd (1/s) and the affinity Kd (M). Table 8 includesFKBP12 direct binding K_(d) (nM) values of selected compounds; withcompounds having a FKBP12 direct binding K_(d) of less than 0.3 nM as A,0.3 nM to 1.0 nM as B, and greater than 1.0 nM as C.

Example 29 SPR Assay to Determine Binding Affinity to FKBP51

Biotinylated avi-FKBP51 was immobilized on a streptavidin chip (CytivaSeries S SA) using a Biacore 8K or 8k+ (Cytiva). To achieve animmobilization level of 2000 RU, 3 μg/ml biotinylated avi-FKBP51 wereinjected for 360 sec at a flow rate of 10 μl/min. Rapalogs were dilutedin DMSO to 100× working concentration. Each Rapalog was 100-fold dilutedin 50 mM HEPES pH 7.5, 150 mM NaCl, 2 mM MgCl₂, 1 mM DTT, 0.05% Tween-20and a serial dilution prepared (8 concentrations, 3-fold dilutions,0.5-1000 nM). Rapamycin was used as reference sample (8 concentrations,3-fold dilutions, 0.5-1000 nM). The compound dilutions were theninjected at 100 uL/min for 120 seconds contact time and with 3600seconds dissociation time with increasing concentrations. 50 mM HEPES pH7.5, 150 mM NaCl, 2 mM MgCl₂, 1 mM DTT, 0.05% Tween-20, 1% DMSO was usedas running buffer. Multi-cycle kinetics data were fit to a 1:1 bindingmodel to measure the association rate ka (1/Ms), the dissociation ratekd (1/s) and the affinity Kd (M).

Table 8 includes FKBP51 direct binding K_(d) (nM) values of selectedcompounds; with compounds having a FKBP51 direct binding K_(d) of lessthan 10 nM as A, 10 nM to 100 nM as B, and greater than 100 nM as C.

Example 30 SPR Assay to Characterize Ternary Complex Formation withFKBP12

Biotinylated avi-FKBP12 was immobilized on a streptavidin chip (CytivaSeries S SA) using a Biacore 8K or 8k+ (Cytiva). To achieve animmobilization level of 100 RU, 0.3 μg/ml biotinylated avi-FKBP12 wereinjected for 80 sec at a flow rate of 10 μl/min. Serial dilution of FRBwas prepared (12 concentrations, 3-fold dilutions, 0.00011-20 μM) andsupplemented with 100 nM of rapalog. A-B-A injection mode was used toensure saturation immobilized FKBP12 with respective rapalog. 100 nMsolution of the respective rapalog was injected before FRB injection for120 sec and during dissociation for 420 sec. The FRB dilutions were theninjected 120 seconds contact time with increasing concentrations.Rapamycin was used as reference sample. 50 mM HEPES pH 7.5, 150 mM NaCl,2 mM MgCl₂, 1 mM DTT, 0.05% Tween-20, 1% DMSO was used as running bufferat a flow rate of 30 μl/min. The multi-cycle kinetics data were fit to a1:1 binding model to measure the association rate ka (1/Ms), thedissociation rate kd (1/s) and the affinity Kd (M). In case of fastassociation and dissociation, steady state affinity analysis followingthe law of mass action was used to determine the affinity Kd (M).

Table 9 includes FKBP12 ternary complex K_(d) (nM) values of selectedcompounds; with compounds having a FKBP12 ternary complex K_(d) of lessthan 300 nM as A, 300 nM to 800 nM as B, and greater than 800 nM as C.

Example 31 SPR Assay to Characterize Ternary Complex Formation withFKBP51

Biotinylated avi-FKBP51 was immobilized on a streptavidin chip (CytivaSeries S SA) using a Biacore 8K or 8k+ (Cytiva). To achieve animmobilization level of 200 RU, 0.6 μg/ml biotinylated avi-FKBP51 wereinjected for 150 sec at a flow rate of 10 μl/min. Serial dilution of FRBwas prepared (12 concentrations, 3-fold dilutions, 0.00011-20 μM) andsupplemented with 100 nM of rapalog. A-B-A injection mode was used toensure saturation immobilized FKBP12 with respective rapalog. 100 nMsolution of the respective rapalog was injected before FRB injection for120 sec and during dissociation for 420 sec. The FRB dilutions were theninjected 120 seconds contact time with increasing concentrations.Rapamycin was used as reference sample. 50 mM HEPES pH 7.5, 150 mM NaCl,2 mM MgCl₂, 1 mM DTT, 0.05% Tween-20, 1% DMSO was used as running bufferat a flow rate of 30 μl/min. The multi-cycle kinetics data were fit to a1:1 binding model to measure the association rate ka (1/Ms), thedissociation rate kd (1/s) and the affinity K_(d) (M). In case of fastassociation and dissociation, steady state affinity analysis followingthe law of mass action was used to determine the affinity Kd (M).

Table 9 includes FKBP51 ternary complex K_(d) (nM) values of selectedcompounds; with compounds having a FKBP51 ternary complex K_(d) of lessthan 300 nM as A, 300 nM to 800 nM as B, and greater than 800 nM as C.

Example 32 mTORC1 Inhibition, mTORC2 Inhibition, Cell Lysis, AlphaLISAExperiments, and Data Analysis

mTORC1 inhibition was determined via analysis of phosphorylation levelsof Phospho-p70 S6 kinase (p70S6K pT389) and Phospho-S6 Ribosomal Protein(pRPS6 pS240/pS244) with the corresponding AlphaLISA kits (PerkinElmerAlpha SF Ultra™ Multiplex phospho (Thr389)/total p70 S6K Assay Kit(Eu/Tb) and AlphaLISA SF Ultra™ p-Ribosomal Protein S6 (Ser240/244)Assay Kit). Thus, PC-3 cells were plated on 96 well Corning clear bottomplates (Cat #3997) in growth medium (DMEM:Ham's F12, basic (CLS CellLines Service GmbH, Cat #820400a), supplemented with additional 5% fetalbovine serum (FBS; Gibco, Cat #10500064) at 1.20E+06 cells/mL andincubated over-night at 37° C., 5% CO₂. On the following day, cells weretreated with growth medium containing increasing compound concentrations(12 points at 3-fold dilutions) and incubated for further 24 hours at37° C., 5% CO₂ before cell lysis.

mTORC2 inhibition was determined via analysis of phosphorylation levelof Phospho-AKT (pAKT pS473) with the corresponding AlphaLISA kit(PerkinElmer, Alpha SF Ultra™ Multiplex p-AKT1/2/3(Ser473)/Total AKT1).PC3 cells were plated on 96 well plates in assay medium (DMEM:Ham's F12,basic (CLS Cell Lines Service GmbH, Cat #820400a), supplemented withadditional 10% FBS at 1.20E+06 cells/mL and incubated over-night at 37°C., 5% CO₂. On the following day, cells were treated with assay medium(10% FBS) containing increasing compound concentrations (12 points at3-fold dilutions) and incubated for 6 hours at 37° C., 5% CO₂.Thereafter, medium was aspirated and cells were rinsed with PBS. In thefollowing, cells were treated with compound dilutions in starvationmedium (DMEM:Ham's F12, basic; without FBS) for further 18 h at 37° C.,5% CO₂. Then, immediately prior to cell lysis, cells were treated with12% FBS for 15 min.

After performing experiments according to mTORC1 and mTORC2 protocols,cells were harvested in lysis buffer supplied with the AlphaLISA kits,additionally enriched with Roche cOmplete™ Protease Inhibitor Cocktail(Cat #CO-RO). Thus, cells were lysed using 50 μL of the lysis buffer andincubated for 60 min at 4° C. while shaking. After centrifugation at4000 rpm for 5 min, experiments were performed according to theAlphaLISA manufacturer's protocol.

Ten microliters of cell lysates were mixed with the acceptor mix. Afterincubation for 2 h at room temperature, the donor mix was added. Afteradditional incubation at room temperature for 2 hours, AlphaLISA signalwas read on PHERAstar® FSX (BMG Labtech) with AlphaPLEX module. Percentinhibition was calculated via ExcelFit standard algorithm, based on highcontrol (cells incubated with vehicle/DMSO) and low control (mTORC1:cells incubated with 0.1 μM rapamycin; mTORC2: cells incubated with 1 μMrapamycin). All IC50 experiments were conducted in triplicates withrapamycin and vehicle controls.

Data Analysis

-   Percentaged activity/inhibition was calculated via application of    the equations:

%-activity=100*((Sample−Low control)/(High control−Low control))

%-inhibition=100*(1−((Sample−Low control)/(High control−Low control)))

-   Sample=Assay signal (phospho-protein normalized to total protein) at    respective compound concentration-   High Control=Assay signal in presence of vehicle/DMSO-   Low Control=Assay signal cells in presence of 0.1 μM (mTORC1) or 1    μM rapamycin (mTORC2)

EC50 values were calculated by ExcelFit standard algorithm. All IC50experiments were conducted in triplicates with rapamycin and vehiclecontrols (six high /low controls per plate).

Table 10 includes IC₅₀ (nM) values for mTORC1 as measured by inhibtionof p70S6K pT389 levels by selected compounds; with compounds having anIC₅₀ for mTORC1 of <0.1 nM as A, 0.1 nM to 0.8 nM as B, and greater than0.8 as C. Table 10 also includes mTORC2% inhibition at 1 uM. For mTORC2:A≤20% inhibition at 1 micro Molar (uM), B>20% and less than 40%inhibition at 1 uM, C≥40% and less than 60% inhibition at 1 uM, D≥60%inhibition at 1 uM.

TABLE 8 FKBP12 and FKBP51 direct binding K_(d) values Compound FKBP12K_(d) (nM) FKBP51 K_(d) (nM)  1 C B  2 A B  3 B C  4 A B  5 A B  6 A A 7 A B  8 A B  9 A A 10 B B 11 B B 12 B B 13 A B 14 B B 15 A B 16 A B 17A B 18 B B 19 B C 20 A C 21 A B 22 A C 23 A B 24 A B 25 A B 26 A C 27 AB 28 A B 29 A C 30 A B 31 A B 32 A B 33 A B 34 A B 35 A A 36 A C 37 C 38B B 39 B C 40 C C 41 B C 42 C C 43 C C 44 C C 45 C C 46 C C 47 C C 48 CC 49 A C 50 C C 51 C C 52 B C 53 B C 54 C C 55 A C 56 A C 57 C B 58 B 59A B 60 C C 61 A C 62 C C 63 C 64 B C 65 A B 66 B B 67 A B 68 A B 69 B BRapamycin A A

TABLE 9 FKBP12 and FKBP51 ternary complex formation K_(d) values FKBP12ternary FKBP51 ternary Compound # complex K_(d) (nM) complex K_(d) (nM) 1 B A  2 A B  3 C C  4 A B  5 C C  6 C C  7 A B  8 B B  9 A A 10 B B 11B B 12 B B 13 B C 14 C C 15 A C 16 B C 17 B C 18 B B 19 C C 20 B C 21 CC 22 C C 23 C C 24 B B 25 B C 26 C C 27 C C 28 C C 29 C C 30 C C 31 C C32 B C 33 C C 34 C C 35 C C 36 B C 37 B C 38 C C 39 B C 40 B C 41 C C 42B C 43 A A 44 A C 45 A A 46 B B 47 A C 48 B C 49 B C 50 B C 51 B C 52 AC 53 A C 54 A C 55 B C 56 B C 57 B C 58 B A 59 A B 60 A C 61 A C 62 A C63 B C 64 A A 65 B C 66 C C 67 B C 68 A C 69 B C

TABLE 10 mTORC 1 and mTORC 2 Compound mTORC1 IC50 (nM) mTORC2 %inhibition at 1 uM  1 B A  2 A A  3 C A  4 A A  5 B A  6 B A  7 B B  8 BB  9 A C 10 B A 11 B A 12 C A 13 B A 14 C A 15 B A 16 B B 17 B A 18 B A19 C B 20 B B 21 C A 22 B A 23 C A 24 B A 25 B A 26 C A 27 C A 28 B B 29C A 30 C A 31 B A 32 B A 33 C A 34 C A 35 C A 36 B B 37 C B 38 B A 39 BB 40 B A 41 C A 42 C A 43 C C 44 B C 45 C B 46 B B 47 C B 48 C A 49 C B50 C B 51 C A 52 B B 53 B C 54 B B 55 B B 56 B C 57 C B 58 C B 59 A D 60B B 61 A B 62 C C 63 C C 64 B C 65 B A 66 B A 67 B B 68 A C 69 B BRapamycin A D

1. A compound represented by the structure of Formula I:

or a pharmaceutically acceptable salt thereof, wherein: R¹ is selectedfrom

R² is selected from hydrogen and an optionally substituted C₁-C₆ alkoxy,wherein substituents are independently selected at each occurrence fromhydroxy, halogen, —CN, —NO₂, C₁-C₆ alkoxy, 3- to 10-memberedheterocycle, and C₃₋₁₀ carbocycle, wherein the 3- to 10-memberedheterocycle and C₃₋₁₀ carbocycle are each optionally substituted withone or more substituents independently selected from hydroxy, halogen,—CN, —NO₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, and C₁-C₆alkoxy; R³ is selected from hydrogen and an optionally substituted C₁-C₆alkoxy, wherein the substituents are independently selected at eachoccurrence from hydroxy, halogen, —CN, —NO₂, C₁-C₆ alkoxy, 3- to10-membered heterocycle, and C₃₋₁₀ carbocycle, wherein the 3- to10-membered heterocycle and C₃₋₁₀ carbocycle, are each optionallysubstituted with one or more substituents independently selected fromhydroxy, halogen, —CN, —NO₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆hydroxyalkyl, and C₁-C₆ alkoxy; and R^(4′) is selected from

R⁵ is selected from hydrogen, hydroxy, and an optionally substitutedC₁-C₆ alkoxy, wherein substituents are independently selected at eachoccurrence from hydroxy, halogen, —CN, —NO₂, C₁-C₆ alkoxy, 3- to10-membered heterocycle, and C₃₋₁₀ carbocycle, wherein the 3- to10-membered heterocycle, and C₃₋₁₀ carbocycle are each optionallysubstituted with one or more substituents independently selected fromhydroxy, halogen, —CN, —NO₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆hydroxyalkyl, and C₁-C₆ alkoxy; R⁶ and R⁷ come together to form

R²² is selected from optionally substituted C₁-C₆ alkyl, optionallysubstituted 3- to 10-membered heterocycle, and optionally substitutedC₃₋₁₀ carbocycle, and —P(═O)(R²⁴)₂; R²⁴ is optionally substituted C₁-C₆alkyl; R¹⁰⁰ is selected from: hydrogen and —(CH₂—CH₂-G)_(y)-V; and C₁₋₁₀alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, wherein each of which is optionallysubstituted with one or more substituents independently selected fromhalogen, —OR³¹, —SR³¹, —N(R³¹)₂, —C(O)R³¹, —C(O)N(R³¹)₂, —N(R³¹)C(O)R³¹,—C(O)OR³¹, —OC(O)R³¹, —S(O)R³¹, —S(O)₂R³¹, —P(O)(OR³¹)₂, —OP(O)(OR³¹)₂,—NO₂, —CN, C₃₋₂₀ carbocycle and 3- to 20-membered heterocycle; and C₃₋₂₀carbocycle and 3- to 20-membered heterocycle each of which is optionallysubstituted with one or more substituents independently selected fromhalogen, —OR³¹, —SR³¹, —N(R³¹)₂, —C(O)R³¹, —C(O)N(R³¹)₂, —N(R³¹)C(O)R³¹,—C(O)OR³¹, —OC(O)R³¹, —S(O)R³¹, —S(O)₂R³¹, —P(O)(OR³¹)₂, —OP(O)(OR³¹)₂,—NO₂, ═O, ═S, ═N(R³¹), —CN, C₁₋₆ alkyl, C₁₋₆ alkyl-R³¹, C₂₋₆ alkenyl,and C₂₋₆ alkynyl; each G is independently selected from —O—, —NR³²—,—S—, or —SO₂—; y is selected from 3-20; V is selected from hydrogen andoptionally substituted —C₁-C₆ alkyl; R^(110′) is selected from:—S(O)R^(51′), and —S(O)₂R^(51′); each R³¹ is independently selected fromhydrogen, and C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀carbocycle, and 3- to 10-membered heterocycle, each of which isoptionally substituted with one or more substituents independentlyselected from halogen, —OH, —CN, —NO₂, —NH₂, ═O, ═S, C₁₋₁₀ alkyl, —C₁₋₁₀haloalkyl, —O—C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀carbocycle, and 3- to 10-membered heterocycle; and R³² is independentlyselected at each occurrence from: hydrogen; and C₁₋₁₀ alkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocycle, and 3- to 10-memberedheterocycle, each of which is optionally substituted with one or moresubstituents independently selected from halogen, —OH, —CN, —NO₂, —NH₂,═O, ═S, C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl, —O—C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl,C₂₋₁₀ alkynyl, C₃₋₁₀ carbocycle, and 3- to 10-membered heterocycle;wherein the optional substituents on R²², R²⁴, R^(51′), V, and T areindependently selected at each occurrence from: halogen, —OR³⁰,—N(R³⁰)₂, —(O—CH₂—(CH₂)_(p))_(n)—W, —SR³⁰, —C(O)R³⁰, —C(O)N(R³⁰)₂,—N(R³⁰)C(O)R³⁰, —C(O)OR³⁰, —OC(O)R³⁰, —S(O)R³⁰, —S(O)₂R³⁰, —P(O)(OR³⁰)₂,—OP(O)(OR³⁰)₂, —NO₂, ═O, ═S, ═N(R³⁰), and —CN; C₁₋₁₀ alkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, each of which is optionally substituted with oneor more substituents independently selected from halogen, —OR³⁰, —SR³⁰,—N(R³⁰)₂, —C(O)R³⁰, —C(O)N(R³⁰)₂, —N(R³⁰)C(O)R³⁰, —C(O)OR³⁰, —OC(O)R³⁰,—S(O)R³⁰, —S(O)₂R³⁰, —P(O)(OR³⁰)₂, —OP(O)(OR³⁰)₂, —NO₂, ═O, ═S, ═N(R³⁰),—CN, C₃₋₁₀ carbocycle and 3- to 10-membered heterocycle; and C₃₋₁₀carbocycle and 3- to 10-membered heterocycle each of which is optionallysubstituted with one or more substituents independently selected fromhalogen, —OR³⁰, —SR³⁰, —N(R³⁰)₂, —C(O)R³⁰, —C(O)N(R³⁰)₂, —N(R³⁰)C(O)R³⁰,—C(O)OR³⁰, —OC(O)R³⁰, —S(O)R³⁰, —S(O)₂R³⁰, —P(O)(OR³⁰)₂, —OP(O)(OR³⁰)₂,—NO₂, ═O, ═S, ═N(R³⁰), —CN, C₁₋₆ alkyl, C₁₋₆ alkyl-R³⁰, C₂₋₆ alkenyl,and C₂₋₆ alkynyl; R³⁰ is independently selected at each occurrence fromhydrogen; C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocycle,and 3- to 10-membered heterocycle, each of which is optionallysubstituted with one or more substituents independently selected fromhalogen, —OH, —CN, —NO₂, —NH₂, ═O, ═S, C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl,—O—C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocycle, and 3-to 10-membered heterocycle; R^(51′) is independently selected at eachoccurrence from substituted C₁₋₄ alkyl, optionally substituted C₃₋₈carbocycle, optionally substituted 3-10 membered heterocycle,—((CH₂)_(q)—CH₂-D)_(z)-T and optionally substituted C₅₋₃₀ alkyl; q isselected from 1 to 6; each D is independently selected from —O—, —NR³²—,—S—, or —SO₂—; z is selected from 1-20; T is selected from hydrogen andoptionally substituted —C₁-C₆ alkyl; each p is selected from 1 or 2;each n is selected from 3-7; and each W is selected from hydrogen, —OH,—C₁-C₄ alkyl and —O(C₁-C₄ alkyl).
 2. The compound or salt of claim 1,wherein R²² is selected from substituted C₁-C₆ alkyl.
 3. The compound orsalt of claim 2, wherein the substituents on R²² are independentlyselected from —OR³⁰, —(O—CH₂—(CH₂)_(p))_(n)—W, —S(O)R³⁰, —S(O)₂R³⁰, ═O,═S, ═N(R³⁰), and —CN.
 4. The compound or salt of claim 1, wherein R²² isselected from optionally substituted C₁-C₆ alkyl.
 5. The compound orsalt of claim 4, wherein the optional substituents on R²² areindependently selected from —OR³⁰, —S(O)₂R³⁰, and ═O.
 6. The compound orsalt of claim 5, wherein the optional substituents on R²² areindependently selected from —OR³⁰, and —S(O)₂R³⁰.
 7. The compound orsalt of claim 6, wherein R³⁰ of —OR³⁰ and —S(O)₂R³⁰, are independentlyselected from hydrogen and C₁₋₁₀ alkyl, wherein the C₁₋₁₀ alkyl isoptionally substituted with one or more substituents independentlyselected from halogen, —OH, —CN, —NO₂, —NH₂, ═O, ═S, —C₁₋₁₀ haloalkyl,—O—C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocycle, and 3-to 10-membered heterocycle.
 8. The compound or salt of 7, wherein R³⁰ of—OR³⁰ and —S(O)₂R³⁰ is independently selected at each occurrence fromhydrogen and C₁₋₁₀ alkyl.
 9. The compound or salt of claim 1, wherein R¹is selected from


10. The compound or salt of claims 9, wherein R¹ is selected from


11. The compound or salt of claim 1, wherein R¹⁰⁰ is selected fromhydrogen and C₁₋₁₀ alkyl.
 12. The compound or salt of claim 11, whereinR¹⁰⁰ is selected from hydrogen.
 13. The compound or salt of claim 1,wherein R^(110′) is selected from: -S(O)₂R^(51′).
 14. The compound orsalt of claim 1, wherein R^(51′) is selected from substituted C₁₋₄ alkyland saturated C₃₋₆ carbocycle.
 15. The compound or salt of claim 14wherein C₁₋₄ alkyl of R^(51′) is substituted with one or moresubstituents independently selected from —OR³⁰, and saturated C₃₋₆carbocycle.
 16. The compound or salt of claim 15, R³⁰ of —OR³⁰ forR^(51′) is selected from hydrogen and C₁₋₁₀ alkyl, wherein the C₁₋₁₀alkyl is optionally substituted with one or more substituentsindependently selected from halogen, —OH, —CN, —NO₂, —NH₂, ═O, ═S, C₁₋₁₀alkyl, —C₁₋₁₀ haloalkyl, and —O—C₁₋₁₀ alkyl.
 17. The compound or salt ofclaim 16, wherein R³⁰ of —OR³⁰ for R^(51′) is selected from C₁₋₁₀ alkylwherein the C₁₋₁₀ alkyl is optionally substituted with one or moresubstituents independently selected from —O—C₁₋₁₀ alkyl.
 18. Thecompound or salt of claim 17, wherein R^(4′) is selected from


19. The compound or salt of claim 1, wherein the compound is selectedfrom

or a pharmaceutically acceptable salt of any one thereof.
 20. Thecompound or salt of claim 1, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 21. The compound or saltof claim 1, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 22. The compound or saltof claim 1, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 23. The compound or saltof claim 1, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 24. The compound or saltof claim 1, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 25. The compound or saltof claim 1, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 26. The compound or saltof claim 1, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 27. The compound or saltof claim 1, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 28. The compound or saltof claim 1, wherein the compound is

or a pharmaceutically acceptable salt of any one thereof.
 29. Apharmaceutical composition comprising a compound or salt of claim 1 anda pharmaceutically acceptable excipient.
 30. A method of treating asubject with a chronic disease wherein the subject would benefit frominhibition of the activity of mTORC1, comprising administering to thesubject a pharmaceutical composition of claim 29.